Pediatric Oncologic Emergencies 

The causes underlying most emergencies that occur in the field of pediatric oncology fall into 4 main etiologic categories, as follows:

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

Each of these types of emergency causes may result in an additional emergency (ie, pain), which is best reviewed independently.^[1]

Relevant clinical guidelines include the following:

• Practice parameters for colon cancer^[2]
• 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline^[3]
• Thrombocytopenia^[4]

For more information, see Hyperviscosity Syndrome, Brain Neoplasms, Lung Neoplasms, Spinal Cord Neoplasms, and Tumor Lysis Syndrome.

Many metabolic and endocrinologic problems can potentially occur in patients with cancer. Tumor lysis syndrome (TLS) is the most common of these problems in the pediatric population, and emergency therapy is frequently required despite substantive prophylaxis. Hypercalcemia, hyponatremia, hypoglycemia, adrenal failure, and lactic acidosis are relatively common.

Tumor lysis syndrome

TLS is defined as a metabolic triad of hyperuricemia, hyperkalemia, and hyperphosphatemia. Renal failure and symptomatic hypocalcemia are secondary complications associated with TLS.^{[5, 6]}

The primary triad results from the 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 a rapid tumoral response to therapy. These conditions are frequently present in the context of acute lymphoid leukemia (ALL), acute myelogenous leukemia (AML), high-grade lymphoma (eg, Burkitt lymphoma), or after initial chemotherapy for some large solid tumors.

Uric acid is derived from the breakdown of nucleic acid and results from catabolism of hypoxanthine and xanthine by xanthine oxidase. Potassium and phosphate are present naturally in the cytoplasm of tumor cells at concentrations substantially higher than that 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 downregulation of calcium in the context of hyperphosphatemia. An elevated level of uric acid, potassium, phosphate, or LDH before the start of chemotherapy indicates present or impending TLS. Therapy is given on both a prophylactic and an emergency basis.

Prophylaxis is appropriate for pediatric patients with leukemia, lymphoma, or a large and particularly anaplastic solid tumor in whom TLS may be present at the time of diagnosis. It is directed at maximizing the excretion of released intracellular contents and at minimizing the production of uric acid.

Prophylaxis treatment may begin hours or days before the start of chemotherapy, and it includes the limitation of both potassium and phosphate intake. Other essential aspects of prophylaxis are hydration, alkalization, reduction of the uric acid level, and electrocardiographic (ECG) monitoring.

The purpose of hydration is to maximize renal excretion of potassium, phosphate, and uric acid. The optimal hydration volume for a pediatric patient is twice the normal maintenance requirement; it may be increased to as much as 4 times the maintenance volume as necessary and as tolerated.

Although oral (PO) hydration is possible, intravenous (IV) therapy is more reliable and is therefore preferred. A 5% solution of dextrose in water (D5W) with one-fourth isotonic sodium chloride solution (40 mEq/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.

Uric acid is less soluble in acidic environments than in alkaline environments; therefore, alkalization inhibits the precipitation of uric acid crystals in the renal tubules. Sodium bicarbonate is added to IV fluids to maintain a urine pH of 7-8.

At first, a sodium bicarbonate concentration of 40-60 mEq/L should be added to the patient’s IV hydration fluids. This concentration should be adjusted as necessary to maintain an appropriate urine pH level. However, overly intensive alkalization exacerbates the precipitation of both calcium phosphate and xanthine. Alkalization may be discontinued when the uric acid level is no longer rising and when it is in the reference range.

Regarding reduction of the uric acid level, allopurinol inhibits xanthine oxidase and decreases the production of uric acid. The dosage for allopurinol is 10 mg/kg/d or 200-300 mg/m²/d administered PO or IV in 2-4 divided doses, with a maximum dosage of 800 mg/d. The incidence of allopurinol-associated skin rash may increase after 7-10 days of therapy.

Urate oxidase is a relatively new agent that catalyzes the conversion of uric acid to allantoin, a compound 5 to 10 times more soluble than uric acid. Rasburicase (Elitek) is a recombinant form of urate oxidase. The dosage for adult and pediatric patients is 0.15-0.2 mg/kg/d IV infused over 30 minutes for 5-7 days. Urate oxidase is rapidly active, highly effective, and safe for use in children. Increased use of this agent may decrease the need for dialysis.

The most rapid evaluation for symptomatic hyperkalemia is accomplished by means of bedside ECG and serial assessment of T-wave morphology; an ECG is usually obtained at the patient’s bedside within 15 minutes. Serum potassium levels are usually determined most rapidly by measuring arterial or venous blood gases. (Blood gas electrolyte levels are usually obtained within 30 min.) Regardless, metabolic evaluation should include an analysis of serum electrolytes, blood urea nitrogen (BUN), 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 might be required and is often most practical in an intensive care unit (ICU). The frequency of subsequent evaluations should be adjusted as necessary during the first 2-5 days after diagnosis and the start of therapy.

Early monitoring includes a coagulation profile and accurate measurements of the patient’s fluid intake, urine output, and body weight. Serial physical examination is important to assess changes in vital signs, evidence of edema, or signs of electrolyte abnormality (eg, Chvostek or Trousseau sign).

Despite appropriate prophylaxis, emergency interventions are frequently necessary in patients with TLS (see the table below). Intervention beyond the prophylactic measures outlined above is focused on maintaining normal end-organ function. The patient’s specific response to serum abnormalities is best modulated by considering both the absolute serum level and the rate of change.

Table 1. Emergency Management of Tumor Lysis Syndrome (Open Table in a new window)

Compensatory down-regulation of serum calcium levels often occurs in patients with hyperphosphatemia. In this setting, administration of exogenous calcium should be avoided unless the ionized calcium is considerably reduced. A result of more than 50-60 when the serum calcium level is multiplied by the serum phosphate level may lead to precipitation, particularly in the renal tubules. The potential for precipitation is increased because of the elevated urine pH level that is necessary to minimize the precipitation of uric acid.

The effect of hypocalcemia on cardiac activity may be monitored by serially evaluating the corrected Q-T interval on bedside ECGs, and intervention may be considered when prolongation is observed. Effective treatment of patients with specific electrolyte abnormalities often requires an alteration in the composition of the IV fluids being infused. Several hours may pass before an effect is observed.

In addition, treatment critically depends on adequate renal function. Acute renal failure and active TLS necessitate early initiation of renal dialysis, and appropriate care can include modification of the dose and or dosing schedule of any of the chemotherapeutic agents administered to treat the patient’s underlying malignant process.

Hypercalcemia

Abnormalities in calcium levels may be sufficiently severe to constitute metabolic emergencies. Hypercalcemia is encountered more frequently than hypocalcemia. Although the incidence of hypercalcemia has not been estimated accurately, hypercalcemia is notably prevalent in adults with cancer.

Elevated calcium levels are reported in 40-50% of patients with breast cancer or multiple myeloma and in 12.5% of patients with lung cancer. A 29-year retrospective evaluation of pediatric patients indicated an overall incidence of hypercalcemia of 0.4%, though other series of pediatric patients demonstrated rates higher than this.

Regardless of its incidence, hypercalcemia is a metabolic emergency for pediatric patients with cancer. Hypercalcemia has been observed in patients with ALL and non-Hodgkin lymphoma and as a dose-limiting toxicity in 13-cis -retinoic acid treatment of patients with neuroblastoma. Hypercalcemia is also a recognized complication in patients with certain pediatric renal tumors (predominantly mesoblastic nephroma and rhabdoid tumor), astrocytoma, desmoplastic round cell tumor, or solid tumors with clinically significant bone metastasis.

Hypercalcemia is defined as a serum calcium level higher than 10.5 mg/dL. It usually results from increased bone resorption. The observed serum calcium level may be adjusted for the serum concentration of albumin by using the following equation: Corrected calcium concentration (mg/dL) = measured calcium concentration (mg/dL) – serum albumin concentration (g/dL) + 4.

In the absence of elevated serum protein levels, disturbances to other organ systems are observed at levels of more than 12-13 mg/dL. levels higher than 20 mg/dL may be fatal.

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 most commonly associated with an elevation of a similar compound, namely, PTH-related polypeptide (PTHrP). PTHrP binds the PTH receptor but is immunologically distinct from PTH. Hibi and coworkers reported the presence of hypercalcemia and elevated PTHrP levels in 4 (5%) of 83 pediatric patients with early pre–B-cell ALL.^[7]

Hypercalcemia 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 was also suggested in a patient with primary disseminated Ewing sarcoma who presented with hypercalcemia in the context of normal PTH and PTHrP levels that improved after indomethacin treatment.

Although an increased level of osteoclast-activating factor is frequently associated with the hypercalcemia of multiple myeloma, it has not been associated with pediatric malignancy. Several other cytokines are involved in bone resorption and may be related to malignancy-induced hypercalcemia.

Transforming growth factor (TGF)-beta is released as a result of osteoclast activity and increases PTHrP production by tumor cells. levels of tumor necrosis factor (TNF) and interleukin (IL)-6 are often elevated in the context of malignancy and increase osteoclast production and differentiation. The in vivo contribution of these and other cytokines to malignancy-associated hypercalcemia remains unclear.

Clinical manifestations of hypercalcemia include neuropsychological, neuromuscular, gastrointestinal (GI), cardiac, and renal symptoms.

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

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

Traditional treatment of pediatric patients with hypercalcemia and malignancies has relied on forced diuresis and the administration of calcitonin, corticosteroids, and mithramycin (see the table below).

Table 2. Traditional Treatment of Hypercalcemia (Open Table in a new window)

Bisphosphonates are useful for treatment of hypercalcemia. Their chemical structure resembles that of inorganic pyrophosphate, but they are resistant to hydrolysis in an acidic environment. Although their 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 (eg, clodronate, etidronate, tiludronate) are metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP), which accumulate intracellularly and induce osteoclast apoptosis.

Relatively potent nitrogen-containing bisphosphonates (eg, pamidronate, alendronate, risedronate, zoledronate, ibandronate) appear to act as transitional-state analogues of isoprenoid diphosphates to inhibit the 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 treating other malignancy-associated skeletal morbidities, such as pain and osteoporosis. Treatment with bisphosphonates should be considered in all patients with a corrected serum calcium level of 12 mg/dL or more (3 mmol). Two of the most commonly employed agents are etidronate and pamidronate (see the table below).

Table 3. Comparison of Bisphosphonates (Open Table in a new window)

Hyponatremia

Severe hyponatremia, defined as a serum sodium level of less than 125 mEq/L, is a complication in pediatric patients with malignancy. Severe hyponatremia can result from systemic illness, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), or iatrogenic factors acting individually or collectively. Symptoms are primarily neurologic, but early, mild hyponatremia causes no clinically significant symptoms.

Anorexia, nausea, and malaise are the first overt findings. These progress to headache, confusion, lethargy, seizure, coma, and death. Although the central nervous system (CNS) may tolerate a gradual change in serum sodium concentrations, rapid changes of 1-2 mEq/L/h lead to cerebral edema and neurologic dysfunction. Severe, life-threatening symptoms almost uniformly occur when the serum sodium concentration is less than 105 mEq/L or when the level decreases to 120 mEq/L within 24 hours.

Hyponatremia most often results from water retention combined with the administration of normal or excessive amounts of fluid. Water retention is a consequence of the release of antidiuretic hormone (ADH) due to a decrease in the effective circulating intravascular volume.

Hyponatremia can occur in edematous states and in true volume depletion. Hyponatremia associated with edematous states is most common in patients with cancer and may result from liver disease, veno-occlusive disease, infection, drug toxicity, or many other etiologies.

Hyponatremia associated with true volume depletion is relatively uncommon and is typically due to identifiable fluid losses, such as severe diarrhea, bleeding, and drainage of effusions or ascites. In either situation, hyponatremia results from a disproportionate accumulation of water from administered hypotonic fluids.

Patients with hyponatremia are usually oliguric with urine sodium levels of less than 15 mEq/L. Excessive renal salt wasting may also cause hyponatremia and can result from drug-induced nephropathy, adrenal insufficiency, or use of thiazide diuretics. Patients with renal-induced hyponatremia are usually nonoliguric and have inappropriately high urine sodium levels.^[8]

Abnormal release of ADH may also lead to 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.^[9] Hyponatremia was defined as a serum sodium level of < 130 mg/dL. SIADH results from persistent release of ADH and subsequent water retention with an 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 of more than 20 mEq/L. The rate at which hyponatremia develops depends on the rate and volume of fluid administration. SIADH occurs in the context of central nervous system (CNS) disturbances, pulmonary disease, use of specific drugs, and various tumors.

Cyclophosphamide is the chemotherapeutic agent most commonly associated with impaired renal excretion of water (see the image below). This complication is most often observed in patients receiving high-dose regimens more commonly associated with stem cell transplant conditioning (>30 mg/kg or >1 g/m²). However, impaired renal excretion of water is also observed at doses of 10-15 mg/kg in patients with autoimmune diseases.

Vincristine, vinblastine, melphalan, and thiotepa have had similar effects but effect less than those of cyclophosphamide. SIADH associated with vincristine therapy may be coincident with severe vincristine neurotoxicity.

Chemotherapy-induced nausea and emesis also produce clinically significant increases 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 clinically significant hyponatremia. Enhanced ADH activity has also occurred with the administration of morphine, carbamazepine, and other drugs.

SIADH is reported to occur after both major and minor surgical procedures, and 18-27% of patients may be affected after surgery of the head and neck.^[10] 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 who required craniotomy revealed a 12% prevalence of SIADH.

Hyponatremia is also a frequent iatrogenic 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. As an alternative, patients with suprasellar tumors or Langerhans cell histiocytosis may self-hydrate with hypotonic fluids in the setting of diabetes insipidus; this practice may cause hyponatremia.

Treatment of hyponatremia is based on the patient’s symptoms and the underlying pathophysiology. These 2 factors determine the optimal rate at which the serum sodium level should be corrected and the optimal volume of fluid to achieve the correction.

In an asymptomatic patient, serum sodium concentrations should be corrected at a rate of 0.5 mEq/L/h or less during the first 24 hours of intervention or 12 mEq/L total. Rapid correction to 1-2 mEq/L/h is indicated only if a patient is symptomatic and only for the first 1-3 hours of therapy, with the goal of improving the serum sodium concentration to 12-15 mEq/L in the first 24 hours.

Management of fluid volume depends on the underlying pathophysiology. In the setting of true extracellular hypovolemic hyponatremia, saline administration corrects hyponatremia and suppresses ADH secretion, improving free water excretion.

In patients with evidence of fluid retention (eg, edema, 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 by using furosemide with or without salt tablets. Demeclocycline, a tetracycline antibiotic, induces nephrogenic diabetes insipidus and can be used if the aforementioned regimen inadequately controls SIADH.

Other metabolic emergencies

Hypoglycemia, adrenal failure, and lactic acidosis are notably less common in the pediatric population than in the adult population.

Hypoglycemia is often defined as a serum glucose level of less than 40 mg/dL. However, initial symptoms may occur at levels higher than this, particularly if the blood glucose level is decreased rapidly. Symptoms are often worst in the early morning. They 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 may also result from tumoral production of compounds with low molecular weight and nonsuppressible insulinlike activity.

Of these compounds, those best characterized are insulinlike growth factor (IGF)-1, IGF-2, somatomedin A, and somatomedin C. Production of these substances extends beyond islet cell tumors, as evidenced in a report of IGF-2–induced hypoglycemia due to a pediatric renal tumor.^[11] Although excessive glucose use by large tumors is a possible cause of hypoglycemia, limited data support this as an etiology in pediatric patients with malignancies.

A graded response to hypoglycemia is appropriate. Mild hypoglycemia may be best managed by increasing the feeding frequency or, if necessary, giving IV infusions of dextrose-containing solutions. Relatively 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 failure or adrenal insufficiency is rare in pediatric patients with cancer. The usual cause is adrenal suppression from extended use of glucocorticoids at supraphysiologic dosages, combined with an abrupt termination of therapy. Symptoms of adrenal insufficiency are exaggerated in the setting of physiologic stress and can include mild acidosis, hyponatremia, and hypokalemia. Severe circulatory collapse and shock are uncommon.

Lactic acidosis is rare in pediatric patients with malignancy and is most frequently 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 best documented in adults with cancer. Treatment is appropriately directed at the underlying etiology of acidosis. A serum lactate level higher than 4 mEq/L is associated with a poor prognosis.

Hematologic abnormalities that call for emergency treatment result from either abnormal hematopoiesis or coagulopathy.

With respect to hematopoiesis, underproduction of specific cell lines is more common than overproduction. Underproduction is due to disease infiltration of the bone marrow, syndromes of bone marrow failure, or treatment-related myelotoxicity. Underproduction results in anemia, thrombocytopenia, neutropenia, or their combination. Overproduction of hematopoietic tissue is primarily observed as hyperleukocytosis associated with acute leukemia.

Coagulopathy manifests as hemorrhage, thrombosis, or both. Coagulopathy is a primary consequence of disease. It results from a primary toxicity due to treatment, or it is secondary to other known complications.

Supportive care for depressed bone marrow activity

Depression of normal bone marrow activity results in anemia, thrombocytopenia, and neutropenia (see below). These signs are best treated with supportive care, regardless of their 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 cytomegalovirus (CMV) immunity status is known, nonimmunity to CMV should be assumed in pediatric patients with malignancy, and patients should receive blood products from donors without CMV. When the patient’s CMV status is unknown, 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 strain of CMV.

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 the patient’s exposure to blood products. Judicious use of blood products decreases infectious risks and is particularly important for patients with newly diagnosed aplastic anemia in whom engraftment of transplanted stem cells is inversely related to the number of exposures to previous donors.

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

Anemia

Pediatric patients who are not critically ill usually tolerate anemia well and do not require transfusion unless their hematocrit level is less than 20-25% (hemoglobin [Hb] level, 7-8 g/dL), they have no evidence of recovery, or they require transfusion for symptomatic improvement. Transfusion of packed red blood cells (PRBCs) may also 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 substantially increase Hb levels. Once severe anemia develops, patients usually require transfusion.

PRBCs are the blood products of choice for the treatment of patients with anemia. The volume of a single unit varies in the range of 250-300 mL. The hematocrit of an individual unit also varies, in the range of 70-85%. A 10 mL/kg transfusion of PRBCs ideally raises the Hb level 2-3 g/dL (hematocrit, 6-9%). In general, PRBCs 10-15 mL/kg can be transfused safely over 2-4 hours. The 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 5 g/dL or less (hematocrit, < 15%).

Transfusion reactions should be watched for and treated appropriately (see the table below).

Table 4. Common Transfusion Reactions (Open Table in a new window)

Thrombocytopenia

In pediatric patients with cancer, thrombocytopenia results from underproduction or excessive consumption of platelets. Although thrombopoietin has strong positive effects on platelet production and though its use continues in clinical trials, the degree to which this cytokine affect platelet transfusion therapy remains unclear. Therefore, platelet transfusions remain the primary treatment for thrombocytopenia in pediatric patients with cancer.

Platelet transfusions are used both as prophylaxis and as therapy for bleeding. General considerations for the use of platelets in pediatric patients with malignancy include the following points:

• Avoid platelet transfusion in the absence of bleeding if thrombocytopenia is secondary to platelet consumption.
• Consider empiric platelet transfusion in patients with platelet counts lower than 10 × 10⁹/L (< 10,000/µL) if thrombocytopenia results from underproduction.
• Consider empiric platelet transfusion in patients with platelet counts lower than 15-20 × 10⁹/L (< 15,000-20,000/µL) if they have acute nonlymphocytic (myeloid) leukemia (ANLL) and if they 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 lower than 20 × 10⁹/L (< 20,000/µL) if the leukocyte count is lower than 100 × 10⁹/L (>100,000/µL) in patients with ANLL or lower than 300-400 × 10⁹/L (>300,000-400,000/µL) in those with acute lymphoid leukemia (ALL).
• Transfuse platelets in any patient with overt bleeding (not ecchymosis or petechiae) and a platelet count lower than 50 × 10⁹/L (< 50,000/µL) in the context of adequate prothrombin times (PTs), activated partial thromboplastin times (aPTTs), and fibrinogen levels.
• Patients with surgical microvascular bleeding usually require platelet transfusion if their platelet count is lower than 50 × 10⁹/L (< 50,000/µL).
• Lumbar puncture is safe in patients with platelet counts higher than 40-50 × 10⁹/L (>40,000-50,000/µL). Data suggest that lumbar puncture may be safe at platelet counts higher than 10 × 10⁹/L (>10,000/µL). However, this observation has yet to be confirmed and is not considered the standard of care in most institutions where invasive procedures are performed in children with thrombocytopenia.
• If the patient has acute bleeding and known platelet alloimmunization, transfuse platelets slowly, over 2-6 hours.

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 are discussed above (see Supportive care for depressed bone marrow activity).

Studies in adults with normal splenic activity indicate that a dose of 1 platelet U/m² (5.5 × 10¹⁰/m²) increases the peripheral platelet count by 10-12 × 10⁹/L (10,000-12,000/µL). One single-donor plateletpheresis unit contains approximately 4 × 10¹¹ platelets and is equivalent to approximately 6 random-donor platelet units. In patients with active bleeding from thrombocytopenia, an incremental increase of 40-50 × 10⁹/L (40,000-45,000/ µL) is usually sufficient to attain hemostasis.

A rise of less than 5-6.5 × 10⁹/L (< 5000-6500/µL) for each transfused unit per square meter (ie, < 50% of expected) on 2 consecutive transfusions suggests active destruction resulting from alloimmunization, which can be confirmed with 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 after transfusion. No reliable predictors are available to determine which patients are most at risk for developing antiplatelet antibodies. Once present, alloimmunization requires crossmatching or HLA typing of platelets before transfusion.

Neutropenia

Neutropenia is the most common toxic result of myelosuppressive chemotherapy, but it may also result from failure or suppression of the bone marrow. Absolute neutrophil counts (ANCs) lower than 0.5 × 10⁹/L (< 500/µL) are associated with increased risk of infection. Neutropenia persisting longer than 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 (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), if stimulating growth of the underlying malignancy is not a concern. 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 feasible therapeutic modality for patients with neutropenia with active unresponsive bacterial or fungal infection, no reliable criteria help in predicting which patients are likely to benefit from this moderately toxic and expensive therapy.

Hyperleukocytosis

Hyperleukocytosis, defined as a peripheral leukocyte count higher than 100 × 10⁹/L (>100,000/µL), is the most common hematologic overproduction syndrome in pediatric patients with cancer that requires emergency treatment. 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.^[12]

Hyperleukocytosis is a poor prognostic indicator in the setting of ALL or ANLL because it is associated with metabolic and hemorrhagic complications. Respiratory complications are most prominent with elevated leukocyte counts in patients with ANLL. Hemorrhagic complications and death rates increase notably when peripheral leukocyte counts are higher than 100 × 10⁹/L (>100,000/µL) in the context of ANLL and higher than 300-400 × 10⁹/L (>300,000-400,000/µL) in the context of ALL.

When present, clinical manifestations of hyperleukocytosis result from anaerobic metabolism and proliferation of blast cells in the microvasculature. Physical findings result from increased viscosity associated with aggregates of blast cell and thrombi in combination with vascular damage and secondary hemorrhage.

Resultant clinical findings are primarily respiratory and neurologic signs. Respiratory signs include dyspnea and hypoxia. Neurologic signs include focal deficit, ataxia, agitation, confusion, delirium, and stupor. Other signs are plethora, cyanosis, papilledema, and distention of the retinal artery or vein.

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 are noted for each of the risks.

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

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 these therapies 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 specific antileukemic therapy may be delayed and if leukocyte counts are more than 100 × 10⁹/L (>100,000/µL) in patients with ANLL or 300-400 × 10⁹/L (300,000-400,000/µL) 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 data from controlled trials are available to address the empiric use of cytoreductive procedures, such as leukophoresis, before antileukemic chemotherapy is administered in patients with hyperleukocytosis.

Risk of tumor lysis syndrome (TLS) is elevated in the setting of leukocytosis. Prophylactic and emergency treatment regimens in patients with TLS are employed as previously described (see Metabolic Emergencies).

Coagulopathy

Pediatric patients with cancer are likely to have clinically significant abnormalities in procoagulation, inhibitors of coagulation, and fibrinolysis. These abnormalities result in hypocoagulable and hypercoagulable conditions that manifest as hemorrhage or thrombosis. Hemorrhage and thrombosis are considerable problems in the setting of hyperleukocytosis. Hemorrhage is also a notable complication during induction chemotherapy for class M3, M4, or M5 acute myeloid leukemia (AML), even with relatively low peripheral leukocyte counts.

Bleeding predominates in this setting secondary to the relative excess of fibrinolytic proteases compared with prothrombotic thromboplastic materials released from blast cells. Hemorrhage may also result from the 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 (DIC) causes hemorrhage, microangiopathic hemolytic anemia, and thrombosis of various degrees. It is characterized by excessive activation of blood coagulation with the consumption of clotting factors. In children with cancer, DIC is most commonly associated with ANLL induction chemotherapy in which thromboplastic materials are released from leukemic blast cells. DIC also occurs in patients with sepsis or, less frequently, in those with widely disseminated solid tumors.

Diagnosis of DIC is demonstrated by an elevated prothrombin time (PT), an elevated activated partial thromboplastin time (aPTT), and decreased platelet counts. Fibrinogen levels may also be decreased with a concomitant elevation of fibrin monomers or fibrin degradation products.

Primary therapy for DIC consists of supportive care and treatment of the inciting etiology. Patients with clinically 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 by using cryoprecipitate, 1 unit (bag)/10 kg. Hyperfibrinolysis, as evidenced by low antiplasmin levels, is treated with epsilon-aminocaproic acid if evidence of hematuria is lacking.

Thrombosis, as an oncologic emergency, is less uncommon in children than in adults. In the pediatric population, symptomatic thrombosis may be associated with central venous catheters. However, 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 has been identified after L-asparaginase therapy. Thrombotic events are substantially most 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. However, none of these measures accurately predicts the risk of thrombosis in an individual patient.

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

Children with cancer are at increased risk for acute life-threatening infections and acute inflammatory processes as a direct result of their underlying disease, treatment, or both.

Infectious emergencies include infections resulting from bacteria, parasites, mycoplasmata, viruses, and/or fungi. Pneumonitis, pancreatitis, hemorrhagic cystitis, enterocolitis, and tissue necrosis due to the extravasation of chemotherapeutic agents represent the severe inflammatory states that can occur. Patients with both infectious and inflammatory conditions may require emergency treatment, and the conditions are considered independently below.

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 the overgrowth of pathogenic organisms. Alone and combined, 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 (GI) tract, to reactivation of endogenous viruses (eg, herpes simplex virus [HSV]), or to reactivation of latent cysts (eg, Pneumocystis carinii). Patients are secondarily at increased risk for systemic infection due to aerosolized viruses, Legionella species, and fungal spores. The degree of compromise in specific arms of the immune system defines the relative risks of infections with particular agents (see the table below).^[13]

Table 5. Oncology-Associated Immunodeficiency and Predicted Infections (Open Table in a new window)

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/µL to 100-500/µL. The most common etiologic agents are bacteria that colonize the host’s skin and GI tract.

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 0.5 × 10⁹/L (< 500/µL), and fever may be defined as a temperature of more than 38°C twice in 24 hours or a temperature of more than 38.3-38.5°C once. The institution of empiric antibiotic therapy for a patient with neutropenia who is febrile decreases infection-related mortality rates, particularly that related 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 the sites of central venous catheter insertion, the skin, oropharynx, and the perirectal areas is necessary.

Cultures of the blood, skin lesions, and diarrheal stool and a workup involving chest radiography, a complete blood count (CBC), and blood urea nitrogen (BUN), creatinine, transaminase, and serum electrolyte tests are recommended aspects of the initial evaluation. Other cultures, radiologic evaluations, and laboratory studies should be ordered as indicated.

An extensive diagnostic evaluation identifies an established or occult infection in 48-60% of patients.^[14] Bacteremia is present in 10-20% of patients with neutropenia who are febrile. Gram-positive organisms account for about 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, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Enterococcus faecalis, Enterococcus faecium, and Corynebacterium species. Gram-negative isolates of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species are more common than Enterobacter, Proteus, Salmonella, and Acinetobacter species. Anaerobic cocci and bacilli are other common bacteriologic isolates.

The Infectious Diseases Society of America has published guidelines for the use of antimicrobial agents to treat patients with neutropenia who are febrile. (See the Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer.)

According to these guidelines, initial antibiotic therapy should consist of broad-spectrum monotherapy with 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, or hypotension-sepsis syndrome. Vancomycin should be discontinued after 48-72 hours if the clinical course or culture results warrant it.

Antibiotics beyond empiric coverage may be needed to treat a confirmed or suspected focus of infection. Typhlitis or a suspected perirectal abscess should be managed with increased antibiotic coverage for anaerobic organisms. Clostridium difficile enterocolitis requires treatment with metronidazole or oral (PO) vancomycin. Additional coverage should be based on organism sensitivities and clinical syndromes.

Empiric antibiotics are typically discontinued when the patient is afebrile and has an ANC of less than 0.5 × 10⁹/L (>500/µL), if both findings occur within the first 7 days of therapy. Continuation of antibiotics is usually recommended regardless of fever when neutropenia is profound, as indicated by an ANC of less than 0.1 × 10⁹/L (>100/µL).

The treatment of patients who have no evidence of infection and who become afebrile but who remain neutropenic at high ANC levels is controversial. In this situation, clinical practice depends on many factors and ranges from discontinuation of antibiotics to continuation of inpatient treatment with broad-spectrum intravenous (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 because of the increasing incidence of resistant bacteria to the last 2 drugs.

In a relatively large study comparing TMP-SMZ and ofloxacin, investigators reported no difference in the number of gram-positive infections but observed fewer gram-negative infections in the ofloxacin cohort than in the TMP-SMZ cohort.^[15] 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 reduces the number of bacterial infections, the increased bacterial resistance and the lack of reduction in mortality rates argue against antibiotic prophylaxis as routine practice.

The use of antibiotics in a patient with cancer who is febrile but who does not have neutropenia requires special consideration when an indwelling venous catheter is in place. In addition to a complete examination and appropriately 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 during 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 broadly categorized on the basis of morphology as either yeasts or filamentous molds. In children with cancer, infection by these and other opportunistic fungal pathogens has increased since the 1980s. The increase reflects the intensive immunosuppression that results from current antineoplastic regimens.

Candidal organisms are now the fourth most common bloodstream pathogen, and undiagnosed invasive fungal infections are identified increasingly often at autopsy. This observation suggests that fungal infections are underdiagnosed. Consistent with these findings is the result of a series of 61 pediatric autopsies in 1990, which found mycotic infection, and not bacterial infection, to be most common.^[16]

Risk factors for systemic fungal infection have been identified (see the table below).

Table 6. Risk Factors for Systemic Fungal Infection (Open Table in a new window)

The most common presenting symptom in patients with invasive fungal disease and neutropenia is persistent or recurrent fever after defervescence despite broad-spectrum antibiotic therapy. A supporting finding is the relatively low incidence of documented fungal infection in patients with neutropenia who were treated empirically with amphotericin B after 7 days (or, most recently, 4 days) of persistent unexplained fever.

Fungal infections may manifest as focal or disseminated disease. Candida and Aspergillus species are the most common causes of fungal infections in immunocompromised hosts.

Candidal organisms are the most common invasive fungal pathogens in pediatric patients with cancer, accounting for approximately 65% of documented fungal infections. Although Candida albicans is historically the most common pathogen, other species are increasingly prevalent and account for approximately 50% of candidal fungemias. The most common organisms are Candida tropicalis (23%), Candida glabrata (8%), Candida parapsilosis (6%), and Candida krusei (4%).

Prophylactic use of thiazole antifungal agents (fluconazole) is associated with C glabrata and C krusei infection. C tropicalis infection is associated with antileukemic therapies that induce clinically significant mucosal toxicity. Systemic infections caused by candidal species primarily manifest 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 order Mucorales, and other molds also infect severely immunocompromised hosts. Unlike yeast and bacterial pathogens, molds are not part of the typical body flora and are usually not acquired by means of person-to-person contact. Therefore, exposure to spores remains an important risk factor for patients. Aspergillus species and other molds principally cause pneumonia, sinusitis, and cerebral abscess formation.

Antifungal agents are administered as prophylaxis, as empiric therapy, or as specific treatment. Most antifungal agents are administered prophylactically or empirically to minimize the risk of systemic disease. This practice reflects the difficulty of treating established infections. The start of antifungal therapy and the choice of an antifungal agent depend on several factors related to the risk of infection and to the risk of infection by a particular organism.

Antifungal prophylaxis is common for patients undergoing stem cell transplant and for patients receiving severely myelotoxic chemotherapy. The thiazole compound fluconazole is the agent most commonly used, and it is credited with decreasing the rate of systemic candidal infection from 11.4% to 4% in patients undergoing stem cell transplantation.

Although the use of fluconazole has decreased the overall rate of systemic fungal infection, the offending organism, when present, is most commonly a thiazole-resistant Aspergillus organism or a candidal yeast species other than C albicans.

Itraconazole is another thiazole compound. Its spectrum of activity is broader than that of fluconazole. The variable oral bioavailability of itraconazole and its interactions with drugs metabolized by the cytochrome P450 system (particularly cyclosporine and tacrolimus) complicate its use in prevention. Low-dose amphotericin B has also been used for prophylaxis during stem cell transplantation; however, information from prospective randomized trials is insufficient to address the use of this approach compared with 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 unexplained fever persists for 4-7 days despite broad-spectrum antibiotic therapy or when a new fever occurs after defervescence to antibiotics.

Although amphotericin B has been the drug of choice for empiric antifungal therapy, fluconazole may be considered if the clinician strongly suspects that the patient has an infection due to a susceptible Candida species (as may be expected in patients after only 7-10 days of neutropenia), colonization with C albicans, and no previous fluconazole prophylaxis. Otherwise, amphotericin B is recommended.

An amphotericin B dosage of 0.5-0.7 mg/kg/d is appropriate for targeting Candida species, but 1 mg/kg/d is preferred for targeting Aspergillus species and other molds. Amphotericin B has also been used intranasally in an attempt to decrease the rate of fatal infections by Aspergillus species in patients undergoing bone marrow transplantation, but the practice is not widespread.

Treatment of established fungal infections is individualized and often difficult. At present, amphotericin B is the principal agent, but substantial nephrotoxicity and infusion-associated toxicity limit treatment with amphotericin B.

Lipid-associated forms of amphotericin are available and circumvent these treatment-limiting toxicities. Both amphotericin B lipid complex (Abelcet) and liposomal amphotericin (AmBisome) reduce nephrotoxicity, and liposomal amphotericin lowers infusion-related toxicity. Lipid-associated forms of amphotericin B may be administered safely at high doses and decrease the need for dosage reduction.

Lipid-associated forms of amphotericin B are normally administered once daily at an initial dosage of 2.5-5 mg/kg/d IV at a rate of 2.5 mg/kg/h. These preparations are now routinely used in patients intolerant of amphotericin desoxycholate, and they are increasingly used to avoid nephrotoxicity in patients at risk. The latter indication has considerably increased the use of these drugs in the past 5 years.

Although the high doses of lipid-associated amphotericin have been credited with therapeutic salvage after amphotericin desoxycholate fails, data from prospective randomized trials to date are insufficient to establish whether an amphotericin B dosage higher than 1 mg/kg/d has a therapeutic advantage.

Newer antifungal agents include triazole compounds (eg, voriconazole and posaconazole) and echinocandins (a new class of agents that inhibit cell-wall synthesis). Their indications and characteristics differ from those of amphotericin B (see the table below).^[17]

Table 7. Limited Comparison of Antifungal Agents (Open Table in a new window)

The newer azole agents are more tolerable than itraconazole, more broadly active, or both. However, clinically significant drug interactions are possible between the azole agents and other drugs frequently given to pediatric patients with cancer.

The echinocandins possess a third mechanism of antifungal activity and increase the possibility of effective multiagent therapy with synergistic activity. The broad range of therapeutic options and the potential for synergism underscore the importance of effective laboratory susceptibility testing of fungal isolates from individual patients.

The newer antifungal agents are increasingly important for both empiric therapy and the management of established fungal infections. For instance, in prospective multicenter randomized studies, voriconazole and caspofungin were suitable alternatives to liposomal amphotericin B for empiric antifungal therapy in patients with persistent fever and neutropenia.^{[18, 19]} Initial therapy with voriconazole was also demonstrated to be superior to amphotericin B desoxycholate in the treatment of invasive aspergillosis.^[20]

Despite the absence of similar clinical trials focused on pediatric patients, these and other studies will probably lead to the increased use of the newer agents in young patients. Appropriate application of these agents to specific clinical situations will remain an area of active clinical investigation.

Viral infections

Continued dose intensification of chemotherapy treatment regimens and routine use of alternative donors for allogeneic hematopoietic stem cell transplantation has increased the importance of viral infections for pediatric patients with cancer. For instance, adenovirus is a frequently reported nonhepatitis virus associated with fulminant hepatic necrosis in patients receiving bone marrow transplants.

Both adenovirus and BK virus are highly associated with hemorrhagic cystitis. Cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV) infections cause clinically significant morbidity and mortality in patients with cancer. Data from both retrospective and prospective studies indicate that CMV antigenemia, for which preemptive antiviral therapy is required, occurs in as many as 70% of patients who have undergone allogeneic hematopoietic stem cell transplantation.^[21]

Therefore, antiviral agents are necessarily and increasingly used for preemptive and therapeutic indications. Although the development and application of new antiviral agents (eg, valganciclovir^[22] ) has increased in the past 10 years, the application of these agents to pediatric patients with cancer is unclear (see the table below).

Table 8. Comparison of Valganciclovir and Cidofovir With Traditional Antiviral Agents Used in Pediatric Oncology (Open Table in a new window)

Inflammatory emergencies

Pneumonitis, pancreatitis, hemorrhagic cystitis, and extravasation of vesicant chemotherapy products are clinically significant noninfectious inflammatory conditions that require emergency 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. Clinical presentations vary and range from no symptoms 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 irradiation. 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 the standard dosage rate). In the context of systemic chemotherapy, similar changes may occur with radiation doses 25% lower than these.

Specific chemotherapeutic agents are associated with acute lung injury (ALI). Bleomycin is the drug most commonly associated with pneumonitis and fibrosis. Other drugs frequently reported to cause pulmonary injury are carmustine, mitomycin (with or 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 involving drugs not primarily associated with pneumonitis.

An idiopathic pneumonia syndrome has been observed after allogeneic transplantation and may result from minor histocompatibility differences between the donor and the host, as suggested by data from a murine transplant model.^[23] A late effect of allogeneic stem cell transplantation is pulmonary fibrosis, which may result from chronic graft-versus-host disease (GVHD) or early acute inflammation.

Transfusion-related ALI (TRALI) is characterized by noncardiogenic pulmonary edema variably associated with respiratory distress and hypoxia after transfusion of a blood product. It results from granulocyte-agglutinating anti–human leukocyte antigen (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, prominent presenting clinical features were emesis or excessive nasogastric drainage (60%), pleural effusion (40%), and abdominal pain (25%).^[24] Of interest, the diagnosis was initially suspected in only 5 of the 40 patients. The reported mortality rate is 5-15%.

Practice guidelines for the care of patients with acute pancreatitis have been published. Physical examination of patients with pancreatitis requires close attention to the patient’s respiratory and cardiovascular status and to findings from abdominal examination. The severity of illness is measured by using the Ranson criteria or the revised Acute Physiology and Chronic Health Evaluation (APACHE II), and the severity is correlated with the outcome.

Laboratory evaluation of patients should include a CBC and tests of amylase, lipase, BUN, serum electrolyte, creatinine, glucose, lactate dehydrogenase (LDH), transaminase, and calcium levels. Abdominal sonography is the initial imaging evaluation and should be performed within 24-48 hours of the patient’s hospitalization. Abdominal computed tomography (CT) is recommended for patients with severe pancreatitis. In the absence of renal insufficiency, use of IV contrast material is recommended.

Treatment is primarily supportive, with an emphasis on bowel rest, fluid resuscitation, and close monitoring of electrolytes, 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.^[25]

To the authors’ knowledge, no prospective randomized trials have been conducted 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, though all of these options 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 that cause hemorrhagic cystitis. An acrolein dye byproduct of their metabolism medicates this effect. The byproduct chemically irritates the bladder mucosa and the renal collecting system.

Clinical symptoms may occur hours, days, weeks, or years after chemotherapy is administered, and once symptoms are established, recurrent bleeding is a common complication. Cystitis progresses from mucosal edema and ulceration to late fibrosis, reflux, and hydronephrosis.

Previous or concurrent pelvic irradiation is a risk factor for hemorrhagic cystitis, and a hemorrhagic cystitis is significantly and positively associated with infection by adenovirus (primarily type 11) and/or by the BK virus. Severe hemorrhagic cystitis occurs in approximately 5% of patients who have undergone bone marrow transplantation, and it is nearly twice as frequent in patients with allogeneic transplants as in patients with autologous transplants.

Optimal treatment of 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 a thiol compound, namely, 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 best treated with hyperhydration, continuous bladder irrigation, platelet transfusion, and treatment of existing coagulopathy. Oxybutynin chloride may provide symptomatic relief of associated bladder spasms. Cystoscopic removal of clots or placement of a suprapubic catheter may be required to manage urinary obstruction.

Bleeding refractory to these measures has been treated by using neodymium:yttrium-aluminum-garnet (Nd:YAG) laser–induced coagulation and local instillation of prostaglandin E₁, alum, silver nitrate, or formalin. Hyperbaric oxygen has been used successfully to treat refractory radiation-induced cystitis. Bladder resection may be required if hemorrhagic cystitis is unresponsive to these measures.

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 on the basis of their local toxicity to subcutaneous tissues (see the table below). Irritant drugs cause pain at the injection site, and they may be associated with local inflammation. Vesicant drugs cause local tissue necrosis or induce blister formation. Nonvesicant drugs produce acute reactions only occasionally.

Table 9. Pediatric Chemotherapeutic Agents That Can Cause Local Tissue Damage If Extravasated (Open Table in a new window)

Tissue damage due to extravasation occurs by means of several mechanisms. Local cells absorb anthracycline drugs, which induce cell death by damaging the DNA. These drugs are then released to similarly affect other cells. Clinically significant anthracycline levels are locally present for weeks to months after extravasation. Local tissue damage from vinca alkaloids and epipodophyllotoxins is attributable to the lipophilic solvents used in the drug preparations and is treated more easily than is damage due to anthracyclines.

Guidelines for local care after extravasation of specific chemotherapeutic agents are available (see the table below).^[26] In general, residual drugs should be aspirated from the infiltrated area. Antidotes, if available, should be administered soon after extravasation. Avoid placing direct pressure on the site to minimize the risk of spreading the agent. Apply heat or cold, as appropriate. Daily evaluation of the affected area is recommended, and consultation with a plastic surgeon may be necessary.

Table 10. Guidelines for Local Care after Extravasation of Common Chemotherapeutic Agents (Open Table in a new window)

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 organ system affected. Neurologic, respiratory, cardiovascular, gastrointestinal (GI), and urologic mechanical emergencies call for immediate medical attention.

Neurologic emergencies

The principal neurologic mechanical emergencies for which emergency medical treatment is required manifest as spinal cord compression,^[6] increased intracranial pressure (ICP) in association with cerebral herniation, and status epilepticus.

Spinal cord compression refers to impingement of the spinal cord or cauda equina, which may occur because of an intramedullary mass from a primary central nervous system (CNS) tumor or because of compression of the thecal sac due to a tumor in the epidural space. This compression most commonly occurs because of direct extension of metastases in the vertebral bone, but it also may result from the growth of a tumor through the intervertebral foramina.

Pain is the first symptom of spinal cord compression and may occur hours or months before neurologic dysfunction begins. Pain associated with epidural compression of the spinal cord is exacerbated when the patient is recumbent and improves when the patient is upright. The pattern of pain is the opposite of that associated with a herniated disk or degenerative spinal disease. Radicular pain is a relatively uncommon 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 tumor, abscess, hematoma, and disk herniation.

Spinal cord compression requires rapid intervention to minimize irreversible dysfunction. Although data from prospective trials are sparse and though few evidence-based therapeutic guidelines are available, acute treatment of cord compression likely requires a combination of corticosteroids, radiation therapy, and surgery. Chemotherapy may also be appropriate in the context of initial disease presentation or chemotherapy-responsive recurrent disease. Optimal treatment requires the collaboration of a medical oncologist, a radiation oncologist, and a 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. Use of systemic steroids is discouraged or contraindicated in favor of local irradiation or diagnostic evaluation if symptoms are suspected to arise from an undiagnosed lymphoproliferative disease.

Otherwise, data from studies of adults suggest that the preferred treatment is high-dose dexamethasone (100-mg bolus followed by 96 mg/d) or moderate-dose dexamethasone (10-mg bolus followed by 16 mg/d). Dexamethasone may be used in combination with radiation therapy and surgery as appropriate.

Local radiation therapy alone may be used for patients who are ambulatory and for pretreatment before paresis occurs. The dosage of radiation therapy is variable and partly determined by the quantity of radiation previous applied locally, the type of tumor present, and the tissue field that is undergoing irradiation. Systemic chemotherapy is appropriate for patients with responsive tumors.

As a primary treatment for cord compression, surgical intervention is restricted to patients with an unstable spine. Decompressive laminectomy was previously a standard treatment though it afforded poor access to approximately 85% of anterior tumors and though it possibly destabilized the spine. Therefore, resection of the vertebral body followed by stabilization has been pursued, but further studies are necessary to best determine the safety and use of the approach.

Nevertheless, surgery is suggested for the treatment of spinal cord compression in patients with no previous history of cancer, in patients with spinal instability or bony compression of the spinal cord, and in patients with previously irradiated areas.

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

If evidence suggests impending cerebral herniation, immediate treatment and diagnostic efforts are necessary. MRI is a superior neuroimaging technique. However, computed tomography (CT) is usually most readily available, and CT scans can be obtained without the use of contrast material to depict both hemorrhage and hydrocephalus.

Mild hyperventilation is the most rapid method for decreasing ICP. A decrease in the partial pressure of carbon dioxide (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 started.

Mannitol is the agent most frequently used to lower ICP. A 20-25% solution of mannitol 0.5-2 g/kg is administered intravenously (IV) over 20-30 minutes. Dexamethasone is most useful when increased ICP results from an intracranial tumor or abscess.

Status epilepticus is defined as prolonged or recurrent seizure activity lasting over 30 minutes during which the patient never regains consciousness. Seizure may result from mechanical or metabolic perturbation of the CNS consequent to a tumor or tumoral therapy. Proper diagnosis and treatment are important because the duration of the seizure is a significant predictor of CNS damage. Diagnostic methods and acute treatments of status epilepticus in children with cancer are equivalent to techniques used to diagnose and treat afebrile seizures 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 it is 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; it is most likely to occur in patients with vocal cord paralysis. Airway compromise in the absence of mediastinal mass or adenopathy is reported in pediatric patients presenting with hemangioma, lymphangioma, cervical and mediastinal teratoma, respiratory papillomatosis, thymoma, and various 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 manifest as wheezing, dyspnea, orthopnea, or increased effort of breathing. Rapid CT scanning is the preferred imaging study in children. Tracheal cross-sectional area, as measured on CT scans, decrease by 35-93% in more than 30% of symptomatic patients.

Although uncommon, symptomatic airway obstruction may be encountered either as a presenting feature or as a complication of refractory disease. Prompt diagnosis by using tissue samples is paramount in patients who initially present with airway compromise, and the institution of appropriate antitumoral therapy is the optimal strategy.

Local radiation therapy may be used, but it can induce inflammation that worsens symptoms transiently. Primary airway support is usually sufficient until definitive therapy is started. Symptomatic relief is the primary objective for patients with airway obstruction as a terminal medical complication. A multimodality approach with radiation therapy, surgery, and pharmacotherapy may be required.

Cardiovascular emergencies

In pediatric patients, mechanical emergencies of the cardiovascular system 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 cardiovascular emergency in pediatric cancer patients is tamponade resulting from malignant or reactive pericardial effusion. Although vascular compression from a tumor mass frequently occurs, it rarely precipitates a medical emergency. The primary exception to this is superior vena cava (SVC) syndrome,^[6] which is often observed in association with a large mediastinal mass.

Cardiac tamponade is defined as the inability of the ventricle to maintain cardiac output because of extrinsic pressure or an intrinsic mass. Although pericardial and pleural effusions are frequently observed, tamponade physiology is a rare complication of pediatric malignancy.

The largest pediatric series reported to date included 9 patients in whom pericardial effusion and tamponade occurred in the context of the following:

• Acute myeloid leukemia (AML) - 3 patients
• Acute lymphoid leukemia (ALL) - 1 patient
• Hodgkin disease - 1 patient
• B-cell lymphoma - 1 patient
• Medulloblastoma - 1 patient
• Desmoplastic small round cell tumor - 1 patient
• Rhabdomyosarcoma - 1 patient

Effusion volumes were 82-500 mL. The quantity of fluid required to induce tamponade depended on the rate of accumulation, with the largest volume accommodated only gradually.

Clinical findings of impending tamponade are similar to those of heart failure and include chest pain, cough, dyspnea, hiccups, nonspecific abdominal pain, and pulsus paradoxus of more than 10 mm Hg. Chest radiographs may reveal the classic water-bag cardiac silhouette. Electrocardiography (ECG) may demonstrate low-voltage QRS complexes and flattened or inverted T waves. Echocardiography is the best single study, 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 when the underlying malignancy is treated.

SVC syndrome results from obstruction of the SVC due to external compression or internal thrombosis. Pediatric patients account for only 0.4-1.4% of reported patients, 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 a result of extension from an indwelling central venous catheter.

Symptoms of SVC syndrome include cough, hoarse voice, chest pain, dyspnea, and orthopnea, as well as a progression to headache, confusion, altered vision, and syncope. Symptoms are aggravated by supine positioning or Valsalva maneuvers. Signs of SVC syndrome are swelling and plethora of the head, neck, and upper extremities. Blood flow in the SVC and thrombi are best assessed with ultrasonography, but rapid CT is recommended for the evaluation of mediastinal masses.

Removal of the indwelling catheter and short-term anticoagulation are usually sufficient to treat a thrombus. Diagnosis by using tissue samples and initiation of definitive anticancer therapy are the objectives if SVC syndrome results from external compression due to a tumor mass. In pediatric patients, emergency local radiation therapy can usually be avoided for a short time in favor of supportive medical treatment.

Gastrointestinal emergencies

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

In addition, intussusception is reported in patients with adenomyoma of the Meckel diverticulum, with hamartoma of the ileum, with acute lymphoblastic leukemia, with leiomyosarcoma, or after resection of a Wilms tumor. GI obstruction has also been reported after 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. Typhlitis, sepsis, or other severe illness may precipitate a temporary ileus.

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

Abdominal ultrasonography or fluoroscopy performed with air-or water-soluble contrast material is the recommended diagnostic procedure. Fluoroscopic procedures can also 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 used in patients with GI emergencies.

In general, large tumor masses that cause GI obstruction because of external compression are best treated with chemotherapy, surgery, radiation therapy, or their combination. Treatment-related complications respond to interim GI decompression and supportive medical treatment.

Urologic emergencies

Like many other mechanical emergencies, urinary obstruction is most common in adults with cancer. Nevertheless, urinary obstruction may occur in the upper or lower urinary tract of children with cancer.

With regard to the upper urinary tract, ureteral obstruction may result from direct tumoral invasion, compression, or encasement. Most tumors that cause ureteral obstruction are genitourinary in origin (eg, rhabdomyosarcoma). Ureteral obstruction is also a long-term complication of external-beam radiation.

Although acute ureteral obstruction is often 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 ultrasonography, CT scanning, radionuclide renography, or retrograde pyelography may be used to diagnose ureteral obstruction. CT best defines extrarenal pathology.

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

Lower urinary tract obstruction may arise from bladder outlet obstruction or urinary retention. Bladder outlet obstruction may result from extrinsic compression by a large pelvic tumor or obstruction by an intrinsic neoplasm at the bladder neck, or it may be a complication of hemorrhagic cystitis. In pediatric patients with malignancy, urinary retention 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. Renal ultrasonography is a rapid and cost-effective method to evaluate the lower urinary tract; however, other modalities are useful for specific indications.

Unless treated on an emergency basis, complete outlet obstruction results in bilateral hydronephrosis and renal insufficiency or failure. Primary therapy is decompression of the bladder by using a small urethral catheter. If the obstruction results from blood clots, use of a large catheter or cystoscopic removal of the clots is necessary. Bladder distention resulting from neurologic dysfunction often necessitates clean, intermittent self-catheterization every 4-6 hours to preserve kidney function and decrease infection rates.