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Library of Congress Cataloging-in-Publication Data

Hastings, Caroline, 1960–

Handbook of pediatric hematology and oncology: Children's Hospital & Research Center Oakland / Caroline A. Hastings, Joseph Torkildson, Anurag

Kishor Agrawal. – 2nd ed.

p. ; cm.

Rev. ed. of: The Children's Hospital Oakland hematology/oncology handbook / Caroline Hastings. 1st ed. c2002.

Includes bibliographical references and index.

ISBN 978-0-470-67088-0 (pbk. : alk. paper)

I. Torkildson, Joseph. II. Agrawal, Anurag Kishor. III. Hastings, Caroline, 1960– Children's Hospital Oakland hematology/oncology handbook. IV. Children's Hospital Medical Center (Oakland, Calif.) V. Title.

[DNLM: 1. Child. 2. Hematologic Diseases–Handbooks.

3. Neoplasms–Handbooks. WS 39]

618.97′06994–dc23

2011048154

A catalog record for this book is available from the British Library.

Preface

The pace of change in the field of pediatric hematology and oncology is staggering. Molecular biology, genomics, and biochemistry have accelerated the accumulation of knowledge and understanding of disease states. Yet the application of this new knowledge to the individual child before you, the work of the physician, is often overwhelming, even for the most experienced practitioner. The course and prognosis for the child is often determined by the rapidity of disease onset, diagnosis, and initial treatment. What is needed is a practical, tested approach to these problems that ensures timely evaluation, competent early care, and avoidance of pitfalls that might prejudice future treatment options. This practical approach is clearly brought by spending time with the patients and their families, and observing the myriad variations that are never mentioned in the large studies or case reports.

This handbook represents the work of my colleagues at Children's Hospital & Research Center Oakland toward this endeavor. The guidelines offered here have been used to train medical students, pediatric residents, and pediatric hematology/oncology fellows for over 20 years. This handbook will give you clinical approaches for common problems in pediatric hematology and oncology, the knowledge to organize and to evaluate the care of your patients, and a framework to incorporate ever-expanding psychosocial needs, clinical studies, medical treatments, and science. All of these are essential components that make up the care of the child with cancer or a blood disease.

Caroline Hastings, M.D.
March 2012

Acknowledgments

We could not be here without the long-standing love and support of our families. On a day to day basis, the patients and their families continue to show us how to live gracefully in even the hardest of times and inspire us to continue to endeavor for improved outcomes. Our experiences have taught us the magnitude of remembering our roles: “to cure sometimes, to relieve often, to comfort always.” (Anonymous, 15^thcentury)

Chapter 1

Approach to the Anemic Child

Anemia is the condition in which the concentration of hemoglobin or the red cell mass is reduced below normal. Anemia results in a physiological decrease in the oxygen-carrying capacity of the blood and reduced oxygen supply to the tissues. Causes of anemia are increased loss or destruction of red blood cells (RBCs) or a significant decreased rate of production. When evaluating a child with anemia, it is important to determine if the problem is isolated to one cell line (e.g., RBCs) or multiple cell lines (i.e., RBCs, white blood cells [WBCs], or platelets). When two or three cell lines are affected, it may indicate bone marrow involvement (leukemia, metastatic disease, and aplastic anemia), sequestration (i.e., hypersplenism), immune deficiency, or an immune-mediated process (e.g., hemolytic anemia and immune thrombocytopenic purpura).

Evaluation of Anemia

The evaluation of anemia includes a complete medical history, family history, physical examination, and laboratory assessment. See Figure 1.1.

Figure 1.1 Diagnostic approach to the child with anemia. (Abbreviations: DBA, Diamond–Blackfan anemia; TEC, transient erythroblastopenia of childhood; RDW, red cell distribution width; FEP, free erythrocyte protoporphyrin; TIBC, total iron binding capacity; G6PD, glucose-6-phosphate dehydrogenase deficiency; DAT, direct antiglobulin test). ^*Refer to Table 1.1 for age-based normal values.

The diagnosis of anemia is made after reference to established normal controls for age (Table 1.1). The blood smear and red cell indices are very helpful in the diagnosis and classification of anemia. It allows for classification by the cell size (MCV, mean corpuscular volume), gives the distribution of cell size (RDW, red cell distribution width), and may give important diagnostic clues if specific morphological abnormalities are present (e.g., sickle cells, target cells, and spherocytes). The MCV, RDW, and reticulocyte count are helpful in the differential diagnosis of anemia. A high RDW, or anisocytosis, is seen in stress erythropoiesis and is often suggestive of iron deficiency or hemolysis. A normal or low reticulocyte count is an inappropriate response to anemia and suggests impaired red cell production. An elevated reticulocyte count suggests blood loss, hemolysis, or sequestration.

Table 1.1 Red blood cell values at various ages.^a

a. Compiled from the following sources: Dutcher TF. Lab Med 2:32–35, 1971; Koerper MA, et al. J Pediatr 89:580–583, 1976; Marner T. Acta Paediatr Scand 58:363–368, 1969; Matoth Y, et al. Acta Paediatr Scand 60:317–323, 1971; Moe PJ. Acta Paediatr Scand 54:69–80, 1965; Okuno T. J Clin Pathol 2:599–602, 1972; Oski F, Naiman J. Hematological Problems in the Newborn, 2nd ed., Philadelphia: WB Saunders, 1972, p. 11; Penttilä I, et al. Suomen Lääkärilehti 26:2173, 1973; and Viteri FE, et al. Br J Haematol 23:189–204, 1972. Cited in: Rudolph AM (ed). Rudolph's Pediatrics, 16th ed., Norwalk, CT: Appleton & Lange, 1977.
Abbreviation: MCV, mean corpuscular volume.

The investigation of anemia requires the following steps:

Table 1.2 The medical history of the anemic child.

Table 1.3 Physical examination of the anemic child.

Figure 1.2 Evaluation of the child with microcytic anemia. (Abbreviations: FEP, free erythrocyte protoporphyrin; TIBC, total iron binding capacity; DAT, direct antiglobulin test; IBD, inflammatory bowel disease).

Figure 1.3 Approach to the full-term newborn with anemia. (Abbreviations: DAT, direct antiglobulin test; G6PD, glucose-6-phosphatase deficiency; TORCH, toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex virus).

Interventions

Oral Iron Challenge

An oral iron challenge may be indicated in the patient with significant iron depletion, as documented by moderate-to-severe anemia and deficiencies in circulating and storage iron forms (such as total iron-binding capacity [TIBC], serum iron, transferrin saturation, and ferritin). Iron absorption is impaired in certain chronic disorders (autoimmune diseases such as lupus, peptic ulcer disease, ulcerative colitis, and Crohn's disease), by certain medications (antacids and histamine-2 blockers), and by environmental factors such as lead toxicity.

Indications for an oral iron challenge include any condition in which a poor response to oral iron is being questioned, such as in: noncompliance, severe anemia secondary to dietary insufficiency (excessive milk intake), and ongoing blood loss.

Administration of an oral iron challenge is quite simple: first, draw a serum iron level; second, administer a dose of iron (3 mg/kg elemental iron) orally; third, draw another serum iron level 30 to 60 minutes later. The serum level is expected to increase by at least 100 mcg/dL if absorption is adequate. The oral iron challenge is a quick and easy method to assess appropriateness of oral iron to treat iron deficiency—a safer, cheaper yet equally efficacious method of treatment as parenteral iron.

Parenteral Iron Therapy

Due to the potential risks of older parenteral iron preparations (specifically high molecular weight iron dextran), a reluctance remains to use the newer and much safer formulations. The majority of safety data exists with low molecular weight (LMW) iron dextran although many practitioners have moved to newer (and perceived safer) formulations including ferric gluconate and iron sucrose. Three additional compounds have been approved recently, 2 in Europe (ferric carboxymaltose and iron isomaltoside) and 1 in the United States (ferumoxytol). These newer agents have the potential benefit of total dose replacement in a very short and single infusion as compared to ferric gluconate and iron sucrose which require multiple doses. LMW iron dextran is approved as a total dose infusion for adults in Europe but not the United States. Due to the smaller dose generally required in pediatric patients, total iron replacement is feasible in 1 to 2 doses of LMW iron dextran. Calculation of the necessary dose is as follows:

where

The maximum adult dose is 2 mL and each milliliter of iron dextran contains 50 mg of elemental iron. Add 10 mg elemental iron/kg to replenish iron stores (chronic anemia states). Replacement may be given in a single dose, depending on the dose required. See the formulary for further information.

Severe allergic reactions can occur with iron dextran and the low molecular weight product should be preferentially utilized. A test dose (10 to 25 mg) should be given prior to the first dose with observation of the patient for 30 to 60 minutes prior to administering the remainder of the dose. A common side effect is mild to moderate arthralgias the day after drug administration, especially in patients with autoimmune disease. Acetaminophen frequently alleviates the arthralgias. Iron dextran is contraindicated in patients with rheumatoid arthritis.

Iron sucrose or ferric gluconate can be considered in inpatients in which multiple doses are more convenient and feasible than the outpatient setting. With continued usage and safety data, ferumoxytol will likely replace the currently used products due to the much larger maximum dose that can be given, lack of need for a test dose, and excellent side effect profile.

Erythropoietin

Recombinant human erythropoietin (EPO) stimulates proliferation and differentiation of erythroid precursors, with an increase in heme synthesis. This increased proliferation creates an increased demand in iron availability and can result in a functional iron deficiency if not given with iron therapy.

Indications for EPO include end-stage renal disease, anemia of prematurity, anemia of chronic disease, anemia associated with treatment for AIDS, and autologous blood donation. EPO use for the treatment of chemotherapy-induced anemia remains controversial and is not routinely recommended in pediatric patients (see Chapter 25).

The most common side effect of EPO administration is hypertension, which may be somewhat alleviated with changes in the dose and duration of administration.

Typical starting dose of EPO is 150 U/kg three times a week (IV) or subcutaneous (SC). CBCs and reticulocyte counts are checked weekly. Higher doses, and more frequent dosing, may be necessary. Response is usually seen within 1 to 2 weeks. Adequate iron intake (3 mg/kg/d orally or intermittent parenteral therapy) should be provided to optimize effectiveness and prevent iron deficiency.

Transfusion Therapy

Children with very severe anemia (Hgb < 5 g/dL) may require treatment with red cell transfusion, depending on the underlying disease and baseline hemoglobin status, duration of anemia, rapidity of onset, and hemodynamic stability. The pediatric literature is scarce as to the best method of transfusing such patients. However, it appears to be common practice to give slow transfusions to children with cardiovascular compromise (i.e., gallop rhythm, pulmonary edema, excessive tachycardia, and poor perfusion) while being monitored in an ICU setting. Transfusions are given in multiple small volumes, sometimes separated by several hours, with careful monitoring of the vitals and fluid balance. For those children who have gradual onset of severe anemia, without cardiovascular compromise, continuous transfusion of 2 mL/kg/h has been shown to be safe and result in an increase in the hematocrit of 1% for each 1 mL/kg of transfused packed RBCs (based on RBC storage method). The hemoglobin should be increased to a normal value to avoid further cardiac compromise (i.e., Hgb 8 to 12 g/dL). Again, the final endpoint may be dependent on several factors including nature of anemia, ongoing blood loss or lack of production, baseline hemoglobin, and volume to be transfused. Care should be taken to avoid unnecessary exposure to multiple blood donors by maximal use of the unit of blood, proper division of units in the blood bank, and avoidance of opening extra units for small quantities to meet a total volume. See Chapter 5 for product preparation, ordering, and premedication. A posttransfusion hemoglobin can be checked if necessary at any point after the transfusion has been completed. Waiting for “reequilibration” is anecdotal and unnecessary.

Case Study for Review

You are seeing a one year old for their well child check in clinic. As part of routine screening, a fingerstick hemoglobin is recommended.

Suggested Reading

Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program 338–347, 2010.

Bizzarro MJ, Colson E, Ehrenkranz RA. Differential diagnosis and management of anemia in the newborn. Pediatr Clin North Am 51:1087–1107, 2004.

Hermiston ML, Mentzer WC. A practical approach to the evaluation of the anemic child. Pediatr Clin North Am 49:877–891, 2002.

Janus J, Moerschel SK. Evaluation of anemia in children. Am Fam Physician 81:1462–1471, 2010.

Richardon M. Microcytic anemia. Pediatr Rev 28:5–14, 2007.