AUTHOR AND EDITOR INFORMATION

Section 1 of 7  

• Authors and Editors
• Introduction
• Metabolic Emergencies
• Hematologic Emergencies
• Infectious and Inflammatory Emergencies
• Mechanical Emergencies
• References

INTRODUCTION

Section 2 of 7  

• Authors and Editors
• Introduction
• Metabolic Emergencies
• Hematologic Emergencies
• Infectious and Inflammatory Emergencies
• Mechanical Emergencies
• References

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

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Bladder Cancer and Brain Cancer.

METABOLIC EMERGENCIES

Section 3 of 7  

• Authors and Editors
• Introduction
• Metabolic Emergencies
• Hematologic Emergencies
• Infectious and Inflammatory Emergencies
• Mechanical Emergencies
• References

Many metabolic and endocrinologic problems can potentially occur in patients with cancer. Tumor lysis syndrome (TLS) is the most common of these problems found 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. 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 myeloid 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 for patients with TLS

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. Therapy is directed at maximizing the excretion of released intracellular contents and at minimizing the production of uric acid. Prophylactic 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, alkalinization, reduction of the uric acid level, and 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 and may be increased up to 4 times the maintenance volume as necessary and as tolerated. Although oral (PO) hydration is possible, intravenous (IV) therapy is most reliable and 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.

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 7.0-8.0. 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 alkalinization 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.

For monitoring, the most rapid evaluation for symptomatic hyperkalemia is accomplished by means of bedside ECG and serial assessment of T-wave morphology, as 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, 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. Monitoring more frequent than this might be required and is often most practical in an 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 (see Hematologic Emergencies) 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.

Emergency treatment of patients with TLS

Table 1 summarizes emergency treatment of specific abnormalities found in patients with TLS. 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. Emergent Management of Tumor Lysis Syndrome

Compensatory downregulation 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 >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 require 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 acute lymphoblastic leukemia 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 refers to a serum calcium level >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 (in milligrams per deciliter) = measured calcium concentration (in milligrams per deciliter) - serum albumin concentration (in grams per deciliter) + 4.

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

Clinical manifestations of hypercalcemia

Clinical manifestations include neuropsychological, neuromuscular, 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.

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 most commonly associated with an elevation of a similar compound, namely, PTH-related polypeptide (PTHrP). PTHrP binds the PTH receptor, but it is immunologically distinct from PTH. Hibi and coworkers (1997) reported the presence of hypercalcemia and elevated PTHrP levels in 4 (5%) of 83 pediatric patients with early pre–B-cell ALL.

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-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.

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. Table 2 summarizes indications, dosages, and features of these agents.

Table 2. Traditional Treatment of Hypercalcemia

^*No longer available in the United States.

Bisphosphonates are 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 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 analogs 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 analogs 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. Table 3 summarizes the use and activity of etidronate and pamidronate.

Treatment with bisphosphonates should be considered in all patients with a corrected serum calcium level of >12 mg/dL (3.0 mmol).

Table 3. Comparison of Bisphosphonates

Hyponatremia

Severe hyponatremia, defined as a serum sodium level of <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 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 <105 mEq/L or when the level decreases to 120 mEq/L within 24 hours.

Pathophysiology of hyponatremia

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 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 <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.

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 (Berghmans, 2000). 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 >20 mEq/L. The rate at which hyponatremia develops 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 is most often observed in patients receiving high dose regimens more commonly associated with stem cell transplant conditioning regimens (>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 (Mesko, 1997). 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 (Blumberg, 1994).

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 patients with hyponatremia

Treatment is based on the patient's symptoms and 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 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 a goal to improve 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

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

Hypoglycemia

Hypoglycemia is often defined as a serum glucose level of <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 (Korn, 1995). 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 managed best by increasing the frequency of feedings or, if necessary, by administering 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

Adrenal failure or adrenal insufficiency is rare in pediatric patients with cancer. The usual cause is adrenal suppression from the 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

In pediatric patients with malignancy, lactic acidosis is rare and 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 >4 mEq/L is associated with a poor prognosis.

HEMATOLOGIC EMERGENCIES

Section 4 of 7  

• Authors and Editors
• Introduction
• Metabolic Emergencies
• Hematologic Emergencies
• Infectious and Inflammatory Emergencies
• Mechanical Emergencies
• References

Hematologic abnormalities that require emergency treatment result from 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 leukocytosis 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. 

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 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 known, nonimmunity to cytomegalovirus (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 lymphocyte antigens (HLAs).

Anemia

Pediatric patients who are not critically ill usually tolerate anemia well and do not require transfusion unless their hematocrit is <20-25% (Hb level 7-8), unless they have no evidence of recovery, or unless transfusion is necessary to improve symptoms. Transfusion of packed RBCs (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 hemoglobin (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 range of an individual unit also varies, in the range of 70-85%. A transfusion of PRBCs 10 mL/kg 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 (hematocrit <15%).

Table 4 summarizes the etiologies of and therapies for the most common transfusion reactions.

Table 4. Common Transfusion Reactions

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 as prophylaxis and as a treatment 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 <10 X 10⁹L (<10,000/mm³) if thrombocytopenia results from underproduction.
• Consider empiric platelet transfusion in patients with platelet counts <15-20 X 10⁹L (<15,000-20,000/mm³) 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 <20 X 10⁹L (<20,000/mm³) if the leukocyte count is <100 X 10⁹L (>100,000/mm³) in patients with ANLL or <300-400 X 10⁹L (>300,000-400,000/mm³) in those with ALL.
• Transfuse platelets in any patient with overt bleeding (not ecchymosis or petechiae) and a platelet count <50 X 10⁹L (<50,000/mm³) 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 <10 X 50⁹L (<50,000/mm³).
• Lumbar puncture is safe in patients with platelet counts of >40-50 X 10⁹L >40,000-50,000/mm³). Recent data suggest that lumbar puncture may be safe at platelet counts >10 X 10⁹L (>10,000/mm³). 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 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 in Depression of bone marrow activity.

Studies in adults with normal splenic activity indicate that a dose of 1 platelet U/m² (5.5 X 10¹⁰/m²) increases the peripheral platelet count 10-12 X 10⁹L (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 40-50 X 10⁹L (40,000-45,000/mm³) is usually sufficient to attain hemostasis.

A rise of <5-6.5 X 10⁹L (<5000-6500/mm³) 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) <0.5 X 10⁹/L (<500/mm³) 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 is the most common hematologic overproduction syndrome in pediatric patients with cancer that requires emergency treatment. Hyperleukocytosis is defined as a peripheral leukocyte count >100 X 10⁹L (>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 (Wald, 1982). 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 notably increase when peripheral leukocyte counts are >100 X 10⁹L (>100,000/mm³) in the context of ANLL and >300-400 X 10⁹L (>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 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 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 substantially change the viscosity of circulating blood, and platelets may safely be transfused 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 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 >100 X 10⁹L (>100,000/mm³) in patients with ANLL or 300-400 X 10⁹L (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 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.

Metabolic risk

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

Coagulopathy

Pediatric patients with cancer are subject to have clinically 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 considerable problems in the setting of hyperleukocytosis. Hemorrhage is also a notable complication during induction chemotherapy for class M3, M4, or M5 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

Disseminated intravascular coagulation (DIC) is characterized by excessive activation of blood coagulation with the consumption of clotting factors. DIC causes hemorrhage, microangiopathic hemolytic anemia, and thrombosis of various degrees. DIC may contribute to hemorrhagic and thrombotic events. 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 is demonstrated by an elevated PT, an elevated aPTT, and decreased platelet counts. Fibrinogen levels may also 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 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

Thrombosis is relatively uncommon oncologic emergency 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 is accurately predictive of 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.

INFECTIOUS AND INFLAMMATORY EMERGENCIES

Section 5 of 7  

• Authors and Editors
• Introduction
• Metabolic Emergencies
• Hematologic Emergencies
• Infectious and Inflammatory Emergencies
• Mechanical Emergencies
• References

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 (Table 5).

Patients are primarily susceptible to systemic dissemination of endogenous bacteria and fungi that colonize the skin and 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.

Table 5. Oncology-Associated Immunodeficiency and Predicted Infections (adapted from Quadri, 2000)

Bacterial pathogens may induce focal or systemic infections, and the incidence of bacterial infections increases as the ANC decreases from 1000 to 500 to 100/mm³. 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 <0.5 X 10⁹/L (<500/mm³), and fever may be defined as a temperature >38.0°C twice in 24 hours or a temperature >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, the skin, oropharynx, and the perirectal areas is necessary. Cultures of the blood, skin lesions, and diarrheal stool and a workup involving chest radiography and CBCs, and 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 (Hughes, 1997). 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, 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.

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 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer. An update is anticipated in early 2007.) 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. C difficile enterocolitis requires treatment with metronidazole or 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 <0.5 X 10⁹/L (>500/mm³), 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 <0.1 X 10⁹/L (>100/mm³). Controversy exists regarding the treatment of patients who have no evidence of infection and become afebrile but who remain neutropenic at high ANC levels. In this situation, clinical practice depends on many factors and ranges from discontinuation of antibiotics to continuation of inpatient treatment with 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 last 2 drugs.

Investigators in a relatively large study compared TMP-SMZ and ofloxacin and reported no difference in the number of gram-positive infections, but fewer gram-negative infections were observed in the ofloxacin cohort than in the TMP-SMZ cohort (Kern, 1991). 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 bacterial infections, the concern of increased bacterial resistance and lack of reduction in mortality rates are argument 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 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 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.

Fungi are broadly categorized by morphology as 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 treatment regimens. Candidal organisms are now the fourth most common bloodstream pathogen, and undiagnosed invasive fungal infections are identified increasingly at autopsy. This observation suggesting that fungal infections are underdiagnosed. Consistent with these findings is the result of a series of 61 pediatric autopsies in 1990 (Kuzuyama, 1990). Mycotic infection, and not bacterial infection, was most common, as the clinician initially believed. Table 6 lists the major risk factors for fungal infections.

Table 6. Risk Factors for Systemic Fungal Infection

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 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 prophylactic, empiric, or therapeutic treatment. Most antifungal agents are administered prophylactically or empirically to minimize the risk of systemic disease. This practice reflects the difficulty in 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 PO 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 in this setting, fluconazole may be considered if the clinician highly 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. A dosage of 0.5-0.7 mg/kg/d is appropriate to target Candida species, but 1 mg/kg/d is appropriate to target 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 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. The lipid-associated forms of amphotericin 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 are insufficient to know when amphotericin B > 1 mg/kg/d has a therapeutic advantage.

New antifungal agents include triazole compounds such as voriconazole and posaconazole and the echinocandins, a new class of agents that inhibit cell-wall synthesis. Table 7 presents a limited comparison of these agents to traditional forms of amphotericin. The newer azole agents are more tolerable and/or more broadly active than itraconazole. 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 increases the importance of effective laboratory susceptibility testing of fungal isolates from individual patients.

Table 7. Limited Comparison of Antifungal Agents

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 (Walsh, 2002 and 2004). Initial therapy with voriconazole was also demonstrated to be superior to amphotericin B desoxycholate in the treatment of invasive aspergillosis (Herbrecht, 2002). Despite the absence of similar clinical trials focused on pediatric patients, these and other studies will likely 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.

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 (see Hemorrhagic cystitis below). CMV, 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. Therefore, antiviral agents are necessarily and increasingly used for preemptive and therapeutic indications. Although the development and application of new antiviral agents has increased in the past ten years, the application of these agents to pediatric patients with cancer is unclear.

Table 8 provides a limited comparison of valganciclovir and cidofovir to acyclovir, ganciclovir, and foscarnet.

Table 8. Comparison of Valganciclovir and Cidofovir With Traditional Antiviral Agents Used in Pediatric Oncology

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. 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 including 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 (Cooke, 1996). A late effect of allogeneic stem cell transplantation is pulmonary fibrosis, which may result from chronic graft versus host disease or early acute inflammation.

TRALI is characterized by noncardiogenic pulmonary edema variably associated with respiratory distress and hypoxia after 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 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%) (Nguyen, 1988). 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 CBCs and tests of amylase, lipase, BUN, serum electrolyte, creatinine, glucose, 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 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 (Schmittenbecher, 1996). 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 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 administer, 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 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 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 <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 (Ditropan) 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 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 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. 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. Table 9 lists drugs with the highest potential to cause local tissue damage after extravasation. Nonvesicant drugs produce acute reactions only occasionally.

Table 9. Pediatric Chemotherapeutic Agents That Can Cause Local Tissue Damage If They Are Extravasated
 

Table 10 summarizes the antidotes for extravasation of specific chemotherapeutic agents. 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 effected area is recommended, and consultation with a plastic surgeon may be necessary.

Table 10. Guidelines for Local Care after Extravasation of Common Chemotherapeutic Agents
 

MECHANICAL EMERGENCIES

Section 6 of 7  

• Authors and Editors
• Introduction
• Metabolic Emergencies
• Hematologic Emergencies
• Infectious and Inflammatory Emergencies
• Mechanical Emergencies
• References

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, GI, and urologic mechanical emergencies require immediate medical attention.

Neurologic emerge