The thromboelastogram has been used to investigate the coagulation status of children undergoing spinal fusion,⁸ neurosurgical procedures,⁹ and cardiopulmonary bypass for cardiothoracic procedures.¹⁰ Although the thromboelastogram may provide useful information in the surgical setting to evaluate fibrinolysis, hypercoagulability, and other coagulation perturbations, its use is usually limited to clinical scenarios with dynamic coagulation changes, such as open heart surgery with cardiopulmonary bypass and liver transplantation. Platelet function analyzer (PFA-100) analysis is an additional test that is increasingly used for the assessment of platelet abnormalities, and it has the benefit of avoiding some of the difficulties of obtaining a bleeding time in children. Although several studies suggest PFA-100 analysis is equivalent or superior to the bleeding time for detecting bleeding abnormalities, there is no consensus about its role in preoperative screening.¹¹ With the increasing use of newer agents that modify platelet function (e.g., platelet G protein–coupled receptor P2Y12 antagonists, glycoprotein GPIIb-IIIa complex antagonists), clinicians must understand that the thromboelastogram, PFA-100, and other methods for assessing platelet function may vary in their ability to monitor the effects of these agents and those of cyclooxygenase inhibitors.¹²

Guidelines for Transfusion

Critical analyses of the risks and benefits of transfusions in infants and children in the perioperative period have resulted in fewer transfusions. Even for infants and children in intensive care, a restrictive transfusion threshold (i.e., 7 g/dL) reduces transfusions without increasing morbidity compared with a liberal threshold (i.e., 9.5 to 10 g/dL).¹³ Data from the United Kingdom’s national audit of clinical transfusion, the Serious Hazards of Transfusion (SHOT), indicate that infants and children younger than 18 years of age are at greater risk for adverse transfusion-related reactions (37 and 18 in 100,000, respectively) than are adults (13 in 100,000). Most events were error related, such as administrative, laboratory, clinical judgment, and handling errors.¹⁴

Guidelines for RBC transfusion for infants and children in the perioperative setting should be consistent with those established by the American Society of Anesthesiologists Task Force on Blood Component Therapy, which propose that transfusion is not indicated for hemoglobin concentrations higher than 10 g/dL but is indicated for concentrations lower than 6 g/dL.¹⁵ When the concentration is between 6 and 10 g/dL, packed red blood cells (PRBCs) should be transfused based on the child’s vital signs, adequacy of oxygenation and perfusion, acuity and degree of blood loss, and other physiologic and surgical factors. When the concentration exceeds 10 g/dL, the decision to transfuse PRBCs to a neonate or infant should be based on the increased baseline concentrations of hemoglobin, increased oxygen consumption, increased affinity of residual fetal hemoglobin for oxygen, absolute blood volume (i.e., 85 mL/kg for a term neonate and 100 mL/kg for a preterm neonate), and other physiologic and surgical factors applicable to all children. The threshold for transfusing a healthy neonate may be 7 g/dL in some clinical settings, but it may be 12 g/dL or higher for a neonate in other settings, such as significant lung disease requiring mechanical ventilation, chronic lung disease, cyanotic congenital heart disease, or heart failure.¹⁶^–¹⁸ For a preterm infant, the risks of hypovolemia, hypotension, acidosis, and postoperative apnea are magnified in the setting of operative blood loss and anemia. It is impossible to address all of the guidelines in this chapter, but many pediatric hematology and oncology consultants have clearly defined transfusion thresholds for their patient populations that should be reviewed preoperatively.

Guidelines for platelet transfusion have been published by consensus committees from France, the United Kingdom, and the United States; these reports are based on available evidence that has been gathered and critically reviewed (Table 9-2).^15,¹⁹^–²² Without evidence that platelet function is significantly different in the healthy infant and child, these guidelines should be applicable to these patients. The decision to transfuse platelets must take into account underlying medical conditions, platelet transfusion history, current medications, surgical bleeding, surgical interventions (e.g., cardiopulmonary bypass), and all other factors that may affect platelet function and turnover.²³^–²⁷ Sevoflurane and propofol suppress²⁸ and enhance platelet aggregation in vitro.²⁹ Despite these effects on platelet aggregation, no change in the bleeding time has been reported, suggesting that the inhibitory effect does not impair hemostasis in vivo.³⁰

TABLE 9-2 Triggers for Platelet Transfusion

Medical Condition or Procedure	Platelet Count (/mm³)
Stable hematology-oncology or chronically thrombocytopenic patient	10,000-20,000
Lumbar puncture in stable leukemic child	10,000
Bone marrow aspiration or biopsy	20,000
Gastrointestinal endoscopy in cancer patient	20,000-40,000
Disseminated intravascular coagulation	20,000-50,000
Fiberoptic bronchoscopy in hematopoietic stem cell transplantation patient	20,000-50,000
Neonatal alloimmune thrombocytopenia	30,000
Major surgery	50,000
Dilutional thrombocytopenia with massive transfusion	50,000
Spinal anesthesia	50,000
Cardiopulmonary bypass	50,000-60,000
Liver biopsy	50,000-100,000
Nonbleeding preterm infant	60,000
Obstetric epidural anesthesia	70,000-100,000
Neurosurgery	100,000

Data from references 19, 20, 23, 26, 27, 265.

Guidelines for the transfusion of other blood products, particularly fresh frozen plasma (FFP) and cryoprecipitate, have been established,^15,^26,³¹ and they are discussed later in the context of coagulation disorders. Indications³² for transfusing FFP are usually limited to the following:

1. Replacement of documented congenital or acquired coagulation factor deficiency when a specific sterilized or combined factor concentrate is unavailable, especially in the setting of anticipated or active bleeding

2. Acquired coagulopathy resulting from massive transfusion

3. Immediate reversal of warfarin’s effect

4. Coagulation support in disease processes such as disseminated intravascular coagulation and thrombotic thrombocytopenic purpura

5. A source of antithrombin III for children deficient of this inhibitor who require heparin

Cryoprecipitate should be administered only for anticipated or active bleeding in children with congenital fibrinogen deficiencies or von Willebrand disease who are unresponsive to desmopressin acetate (DDAVP) or for patients with acquired hypofibrinogenemia (less than 80 to 100 mg/dL) associated with massive transfusion.

Guidelines have been established by the College of American Pathologists and other transfusion study groups for leukocyte reduction of RBC units,¹⁶ irradiation (x-ray or γ-ray) of cellular blood components,³³ and administration of cytomegalovirus-seronegative RBCs (Tables 9-3 to 9-5).¹⁶ These guidelines are valuable when determining the specific choice of blood components that should be ordered and administered in the perioperative setting. For hematologic patients receiving chronic RBC transfusions, an extended phenotypic crossmatch and leukocyte reduction can decrease the risk of developing alloantibodies and transfusion reactions, especially in children of African descent if the local donor pool is primarily derived from Caucasian populations of Northern European descent.³⁴ For oncology patients, updated specific requirements for blood products including leukocyte reduction and irradiation are often indicated and should always be reviewed with oncology specialists.

TABLE 9-3 Indications for Leukocyte-Reduced Red Blood Cell Units

TABLE 9-4 Indications for Irradiation of Cellular Blood Components

Modified from Simon TL, Alverson DC, AuBuchon J, et al. Practice parameter for the use of red blood cell transfusions: developed by the Red Blood Cell Administration Practice Guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med 1998;122:130-8; Treleaven J, Gennery A, Marsh J, et al. Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force. Br J Haematol 2010;152:35-51.

TABLE 9-5 Indications for Cytomegalovirus-Seronegative or Leukocyte-Reduced Red Blood Cells for Prevention of Virus Transmission

Hemolytic Anemias

Anemia commonly manifests in the perioperative setting, and primary hemolytic anemias can present unique and challenging problems for the anesthesiologist. Hemolytic syndromes are a group of disorders in which erythrocyte lysis often leads to anemia. Although RBCs in these disorders may be characterized by abnormal morphology and shorter life span, these parameters may be normal at baseline. Clinical signs of a hemolytic syndrome include anemia, splenomegaly, and jaundice, signs that may be apparent chronically or only during acute exacerbations of a disease process. Hemoglobinuria may be a late finding if massive hemolysis has occurred. Although not well studied, in theory any hemolytic disorder may alter nitric oxide (NO) metabolism.

Many of the hemolytic anemias that are significant to the anesthesiologist result from intracellular defects and can be classified as erythrocyte membrane defects, such as hereditary spherocytosis (HS); enzymatic defects, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency; and qualitative and quantitative defects of hemoglobin, such as sickle cell disease and thalassemia. Other hemolytic anemias that may be encountered in the operating room are largely extracellularly mediated, such as transfusion-related hemolysis and other immune-mediated anemias (alloimmune or autoimmune); this group of anemias is not reviewed here.

Hereditary Spherocytosis

HS, the most common cause of inherited chronic hemolysis in North America and Northern Europe, has a prevalence of approximately 1 to 2 cases per 5000 people, if mild forms of the disease are included.³⁵^–³⁷ First described in 1871, HS is present in many ethnic populations, but rare in African American populations. Because 75% of children inherit the disease in an autosomal dominant pattern, there is often a family history of the disorder, although autosomal recessive mutations, de novo mutations, and incomplete penetrance have been reported.³⁷

Pathophysiology

Abnormalities in any of several erythrocyte membrane proteins, including the β subunit of spectrin, ankyrin, and band 3, can lead to HS. The variety of proteins affected and mutations observed in each gene account for the clinical heterogeneity of the disorder.³⁶ When the erythrocyte loses surface area, it changes from a biconcave disk to a sphere, which alters its stability and flow pattern through the capillaries. The deformity leads to a loss of flexibility in the membrane, which makes it vulnerable to rupture, a condition that is worsened if the membrane surface area decreases by more than 3%.³⁷ Damaged erythrocytes are sequestered in the splenic capillaries, which can lead to splenomegaly. The combination of intravascular and extravascular hemolysis can result in anemia, which induces extramedullary erythropoiesis. The life span of the erythrocyte is reduced from 120 days to just a few days when the RBC membrane has been deformed. If large numbers of damaged erythrocytes are lysed, unconjugated bilirubin is released into the bloodstream, which causes jaundice and possibly gallstones in as many as 60% of children.³⁶ Membrane fragments from hemolytic reactions can lead to disseminated intravascular coagulation. Pulmonary hypertension may occur in the HS population, presumably as a result of hemolysis-induced alterations in NO metabolism.

Clinical and Laboratory Features

Children may present at any age with the triad of anemia, splenomegaly, and jaundice, which often is aggravated by concomitant viral infection. Mild, moderate, and severe forms of HS occur and are characterized by variations in laboratory results and clinical correlates. HS can manifest soon after birth and should be considered in infants who are jaundiced after the first postnatal week; resulting hyperbilirubinemia can sometimes necessitate an exchange transfusion. Mild disease occurs in 20% of children with HS; these children only occasionally present with symptomatic bilirubinate gallstones before adolescence. Approximately 5% of children have severe HS characterized by chronic anemic (hemoglobin concentration less than 8 g/dL) and a need for chronic transfusions. The course of this disease may be complicated by viral infections such as parvovirus B19 infection, which can suppress reticulocyte production ³⁷ and precipitate aplastic crises.

HS is most commonly suspected when numerous spherocytes with loss of central pallor appear on a peripheral smear. A complete blood cell count usually reveals a low hemoglobin and elevated reticulocyte count. Osmotic fragility remains the gold standard for the diagnosis of HS, but this test produces age-related results and must be performed by experienced laboratory technicians in a timely fashion. Increasingly, flow cytometry using eosin-5′-maleimide is being employed for diagnosis because it requires little blood and can be performed after overnight storage.³⁸ As a direct result of chronic hemolysis, unconjugated bilirubin and serum lactate dehydrogenase concentrations increase, and serum haptoglobin concentrations decrease. Thrombocytopenia may develop as a result of hypersplenism.

Perioperative Considerations

Anemia, thrombocytopenia, and splenomegaly are the major considerations for a child with HS undergoing surgery. The most common disease-related operations performed in children with HS are splenectomy and cholecystectomy, individually or in combination, and these procedures may be performed by laparotomy or laparoscopy.

Splenectomy significantly increases red cell survival in most cases and reduces the severity of the anemia and jaundice. It is usually reserved for more severe cases of HS, characterized by severe anemia that require frequent RBC transfusions, poor growth, chronic fatigue, or evidence of extramedullary hematopoiesis (e.g., frontal bossing). Splenic enlargement in a child interested in participating in contact sports is another indication.³⁷ Splenectomy is ideally performed after the age of 6 years because of the increased risk of overwhelming infection by encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B in splenectomized younger children.³⁹ Preoperative vaccination against these organisms is essential unless surgery is required emergently. Guidelines for the indications and duration of postoperative penicillin prophylaxis vary among institutions.³⁶

Splenectomies in children are more frequently performed laparoscopically than by open laparotomy because the former is associated with decreased pain, quicker return of bowel function, shorter hospital stay, and improved cosmetic result. Conversion from laparoscopic to open splenectomy is necessary in fewer than 10% of cases.⁴⁰ Partial splenectomies are increasingly performed because they allow retention of some immune function against bacterial infections in younger children while reducing the sequestration of spherocytes. However, residual splenic tissue can increase in size and necessitate total splenectomy at a later time.^41,⁴² If anemia recurs after splenectomy, it may indicate the presence of accessory splenic tissue that was unrecognized initially. Transient postsplenectomy thrombocytosis marked by dramatic increases in platelet counts may also occur in children,³⁵ in addition to a general increase in the risk of thromboembolic disease.

Gallstones occur in 21% to 63% of children with HS, but cholecystectomy is usually performed only when children are symptomatic with cholelithiasis. Children who undergo splenectomy and who also have radiographically identified gallstones may undergo concurrent cholecystectomy, whether the stones are symptomatic or not.⁴³^–⁴⁵

Table 9-6 summarizes the clinical features and important perioperative considerations for the child with HS undergoing incidental or disease-related surgical procedures.

TABLE 9-6 Perioperative Concerns for Patients with Hereditary Spherocytosis

Preoperative Considerations

Hemoglobin, reticulocyte count, platelet count

History of transfusions and special blood requirements (e.g., extended phenotypic matching, leukocyte reduction)

History of infections, aplastic crises, and presplenectomy vaccinations

Presplenectomy antibiotic prophylaxis and immunization when indicated

Intraoperative Considerations

Appropriate antibiotic coverage

Attention to physiologic effects of laparoscopy on circulatory and respiratory function

Potential for significant blood loss (unusual in splenectomy and cholecystectomy)

Judicious use of regional anesthesia, intramuscular medications, nasogastric tubes, nasal intubation, and other methods when platelet count is low

Limited use of medications with potential bleeding risk (e.g., ketorolac)

Postoperative Considerations

Sequential hemoglobin determinations and platelet counts

Potential thrombocytosis: management as recommended by hematology consultants

Infection risk

Glucose-6-Phosphate Dehydrogenase Deficiency

G6PD deficiency causes hemolysis in the presence of various oxidative stressors. It is the most common enzyme deficiency in humans, affecting approximately 400 million people worldwide. This enzyme deficiency is inherited in an X-linked, recessive fashion. Although males are most commonly affected, females (heterozygous or homozygous for the gene) may have clinical manifestations of the disease. More than 100 variants have been described, including a relatively mild form that affects about 10% of African American males (i.e., G6PD A−) and a more severe form that affects Italians, Greeks, and other populations in the Mediterranean, African, and Asian regions (i.e., G6PD Mediterranean).⁴⁶^–⁴⁸ This deficiency is prevalent in geographic areas where the incidence of malaria is high, presumably because G6PD deficiency may attenuate the severity of malarial infections.

Pathophysiology

G6PD plays an important role in the hexose monophosphate/pentose phosphate shunt, which is essential for normal energy metabolism in erythrocytes. G6PD generates the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). NADPH maintains glutathione in the reduced form (GSH), which reduces peroxides and protects cells from oxidative damage in the course of normal biochemical events or in the event of excess free oxygen radical generation. Superoxide ion or hydrogen peroxide, or both, can oxidize hemoglobin, which then precipitates as insoluble membrane inclusions. These inclusions, together with the oxidative damage to cell membranes, lead to cell damage. Erythrocytes are particularly sensitive to oxidative damage because of their lack of synthetic activity. In the presence of oxidants and free radicals (e.g., produced by infection or by ingestion of certain medications and foods), this cascade of events may precipitate hemolysis in the G6PD-deficient child.^46,⁴⁸

Clinical and Laboratory Features

Clinical symptoms of G6PD deficiency may be deceptively variable, and they may occur in the neonatal period or in older age groups as episodic or chronic hemolytic anemia. Presenting signs include anemia and jaundice; in severe cases, these signs can be followed by lumbar and abdominal pain and by renal failure. Acute illness such as diabetic acidosis or ingestion of a variety of substances may precipitate a hemolytic event (Table 9-7). Hemolysis may range from benign and transitory to severe and life-threatening; the latter situation is more likely if the triggering agent is not eliminated or controlled. Laboratory findings include normocytic anemia, increased reticulocyte count and serum bilirubin concentration, and presence of Heinz bodies in the peripheral blood smear.

TABLE 9-7 Agents That May Precipitate Hemolysis in Patients with Glucose-6-Phosphate Dehydrogenase Deficiency

Antibiotics

Sulfonamides

Trimethoprim-sulfamethoxazole (Bactrim, Septrin)

Antimalarials

Other Medications

Vitamin C (large doses)

Hydralazine

Procainamide

Quinidine

Chemicals

Moth balls (naphthalene)

Methylene blue

Food

Fava (broad) beans

Perioperative Considerations

In the perioperative setting, G6PD deficiency does not usually cause problems if the triggering agents are avoided by susceptible children and the precipitating causes are treated or eliminated (Table 9-8). Monitoring for and treatment of possible complications are appropriate; transfusion is rarely required.

TABLE 9-8 Perioperative Concerns for Patients with Glucose-6-Phosphate Dehydrogenase Deficiency

Preoperative Considerations

History of hemolysis and precipitating factors

Hemoglobin, reticulocyte count

Intraoperative Considerations

Avoidance of triggering agents

Caution in use of high doses of agents that increase methemoglobin, especially in infants

Hemoglobin and urine output in high-risk settings (e.g., cardiopulmonary bypass)

Postoperative Considerations

Hemoglobin, reticulocyte count, urine output if hemolysis

Administration of large or excessive doses of medications such as prilocaine, benzocaine, and sodium nitroprusside may trigger hemolysis in G6PD-deficient children in the perioperative setting.^46,⁴⁸^–⁵⁰ Although these children can reduce methemoglobin that is normally produced by these agents, G6PD-deficient children may not tolerate large amounts of potent oxidizing agents (i.e., superoxide ion and hydrogen peroxide) produced by methemoglobin. Infants may be particularly susceptible to symptomatic methemoglobinemia (because of their low NADPH dehydrogenase activity) and to methemoglobin-induced hemolysis if they are G6PD deficient. Treatment of methemoglobinemia with methylene blue is contraindicated in these infants because the agent itself may precipitate hemolysis.⁴² Hemolysis has occurred during cardiopulmonary bypass in G6PD-deficient children,^50,⁵¹ and methemoglobinemia has occurred in a child with partial G6PD deficiency after application of EMLA cream, a eutectic mixture of local anesthetics.⁵²

Hemoglobinopathies

Sickle Cell Disease

First identified by Herrick about 100 years ago, sickle cell disease is a group of inherited hemoglobinopathies with a diverse worldwide prevalence. The disease affects about 1 in 375 African American and 1 in 20,000 Hispanic births.⁵³ The spectrum of the disease includes sickle cell anemia (HbSS), which accounts for about 70% of the American sickle cell disease population; sickle cell/hemoglobin C disease (HbSC), accounting for about 20%; sickle cell/β-thalassemia (HbSβ), accounting for about 10%; and a host of other, uncommon sickle variants whose prevalence is increasing over time.⁵⁴ HbSβ includes HbSβ⁺ and HbSβ⁰ thalassemias; the distinction depends on whether normal hemoglobin A (HbA) is expressed at all or in only a small concentration. HbSβ⁰, HbSC, and sickle cell/hemoglobin D disease (HbSD) and additional rare forms have the potential to sickle as severely as HbSS. Sickle cell trait (HbAS), in which approximately 40% of hemoglobin is hemoglobin S, occurs in about 8% of African Americans and in a much smaller percentage of Hispanic and other American subpopulations. The sickle gene is found commonly in Africa, Mediterranean areas, southwestern Asia, and other areas where malaria has been historically endemic and for which the gene is protective. Sickle hemoglobinopathies have many implications for perioperative care because they increase perioperative morbidity and mortality.

Pathophysiology

Hemoglobin A is composed of two α- and two β-globin chains. Hemoglobin S is caused by a mutant β-globin gene on chromosome 11, which leads to a single amino acid substitution (valine for glutamate at position 6). Replacement of negatively charged and hydrophilic glutamate by noncharged and hydrophobic valine leads to instability of the hemoglobin molecule and decreased solubility of the molecule when deoxygenated. Hemoglobin polymers form, generating long helical strands and inducing a process that leads to hemoglobin precipitation and hemolysis.⁵⁵

Classically, the pathophysiology and clinical complications of sickle cell disease were thought to be related primarily to the accumulation of sickled erythrocytes in the microvasculature in the setting of factors that promote hemoglobin crystallization (i.e., hypoxia, acidosis, and cellular dehydration) and interfere with peripheral perfusion (i.e., dehydration and hypothermia). This accumulation of sickled cells was thought to compromise the microcirculation, producing ischemia and thereby generating a spiral of red cell sickling and end-organ compromise.

The pathophysiologic process in sickle cell disease is much more complex than originally thought.⁵⁵^–⁵⁷ Inflammation, vascular endothelial adhesion abnormalities, platelets, and coagulation cascade activation all contribute to vaso-occlusive episodes. The sickle red cell membrane, exposed to the destructive oxidant effects of intracellular iron, develops altered transmembrane ion transport pathways, which lead to altered permeability to sodium, potassium, and calcium, causing dehydration of the cell and irreversible sickling.⁵⁸ Membrane abnormalities of phospholipid content also contribute to its deformability, and exposure of phosphatidyl serine facilitates activation of the clotting cascade. These and other factors lead to entrapment of irreversibly sickled red cells in the microcirculation, activation of coagulation and inflammatory pathways, ischemia, and infarction of tissue. At the same time, chronic intravascular hemolysis decreases production of NO, while increased scavenging decreases the bioavailability of NO. The resulting NO deficiency causes endothelial dysfunction and disease complications such as pulmonary hypertension, priapism, and skin ulceration.^58,⁵⁹

Clinical and Laboratory Features and Treatment

Sickle cell disease is a multisystem process involving potentially most organs of the body and often necessitating surgical intervention. Based on data collected in the early 1990s, approximately one third of patients with HbSS disease have progressive disease leading to organ dysfunction and death; about half have significant but less devastating disease; and the remainder have a reasonably stable, slowly progressive clinical course.⁶⁰ Therapeutic interventions and genetic factors account in large part for the differences in outcome. Children with persistence of hemoglobin F (which itself protects against the effects of deoxygenation on red cells) and those with HbSC or HbSβ⁺ have fewer complications than those with HbSS or HbSβ⁰.

Early diagnosis and treatment of sickle cell disease have been facilitated by the widespread use of universal neonatal screening, which was first used in the state of New York in 1975. Most screening programs for sickle cell disease use isoelectric focusing of an eluate from dried blood spot samples, a technique that is also used to screen for other disorders. A few programs use high-performance liquid chromatography. Because a small percentage of children with sickle cell disease are not African American (i.e., Native American, Hispanic, and Caucasian),⁵³ selective screening may not detect all affected infants. As of 2006, all 50 states and the District of Columbia screen all neonates for sickle hemoglobinopathies. Families of infants diagnosed with sickle trait (HbAS) on neonatal screening may not be made aware of the diagnosis, but these infants rarely develop significant clinical problems in the perioperative period.

Affected children born within the United States before universal neonatal screening and those born outside the United States and not receiving regular health care may not have received a diagnosis and appropriate care before surgery. Notwithstanding the controversy over the utility of nonselective preoperative screening,⁶¹ children at risk whose hemoglobin status is unknown preoperatively should be tested with a sickle-screening test, followed by a hemoglobin electrophoretic evaluation if screening is positive. However, infants younger than 6 months of age may have a false-negative screening test result because of presence of fetal hemoglobin, although electrophoresis is diagnostic at all ages. Children older than 10 years of age with a normal hemoglobin value, standard peripheral blood smear, and unremarkable clinical history are probably at a reduced risk for clinically significant hemoglobinopathy.⁶²

Common clinical symptoms of sickle cell disease in children include chronic hemolytic anemia, recurrent vaso-occlusive episodes leading to pain, acute chest syndrome (ACS), infection, renal insufficiency, osteonecrosis, and cholelithiasis. Pulmonary hypertension, priapism, and skin ulcerations are related to the degree of red cell hemolysis.⁶³ Chronic pulmonary and neurologic disease (e.g., stroke) are additional causes of significant morbidity and mortality.⁵⁴ In the perioperative period, the most common complications in sickle cell children include ACS (about 10%), fever or infection (about 7%), vaso-occlusive episodes (about 5%), and transfusion-related events (about 10%).⁶⁴

Chronic hemolytic anemia is a hallmark of HbSS disease. It is characterized by a baseline hemoglobin value of 5 to 9 g/dL (often more than 9 g/dL in HbSC disease), reticulocytosis (5% to 10%), and a distinctive red cell morphology observed on a peripheral smear.⁵⁷ Chronic hemolysis is associated with increased red cell turnover and a propensity to form biliary stones. It may be complicated by other anemic events, such as acute splenic sequestration, typically occurring in infants and young children after a viral illness; and acute aplastic anemia, typically associated with parvovirus B19 infection. For some children, chronic and acute severe anemia are managed with RBC transfusions, although these children are prone to develop alloantibodies to RBC antigens, and untreated iron overload can lead to life-threatening cirrhosis and cardiac failure. Hydroxyurea is used to prevent vaso-occlusive episodes and end-organ damage. Most children are maintained on chronic folic acid therapy to prevent megaloblastic erythropoiesis that can result from the increased red cell production.

Vaso-occlusive episodes in sickle cell disease occur as a result of episodic microvasculature occlusions at one or more sites. The occlusive process occurs most commonly in the phalanges (i.e., dactylitis or hand-foot syndrome), long bones, ribs, sternum, spine, and the pelvis; it also can occur in the mesenteric microvasculature, producing abdominal pain that may mimic a surgical acute abdomen. Vaso-occlusive episodes are managed with hydration, warming, acute and chronic pain management (including opioids, antiinflammatory agents, and complementary modalities), and in-hospital care. It is essential to foster an ideal environment for pain control (e.g., calm, pleasant distractions, supportive personnel and objects). For children who have frequent or severe crises, oral hydroxyurea therapy has been effective in decreasing the frequency of events through several mechanisms, including inhibiting hemoglobin precipitation by increasing fetal hemoglobin concentrations, reducing the white blood cell count, modifying the inflammatory response, and facilitating NO metabolism.^59,^65,⁶⁶ Inhaled NO may prove to be effective therapy for vaso-occlusive episodes.⁶⁷

ACS is characterized by acute respiratory symptoms concurrent with a new infiltrate observed on the chest radiograph.⁶⁸ ACS frequently occurs 2 to 3 days after a vaso-occlusive episode, and although its clinical presentation varies, it often includes fever, tachypnea, cough, and hypoxemia. The process may be self-limited over a period of a few days, or it may progress to respiratory failure (15%) and even death. The inconsistent presentation in part reflects the complex and variable pathogenesis of ACS. An episode may have a single or multiple causes, including infection (i.e., bacteria [often Chlamydia or Mycoplasma], viruses, and mixed flora), pulmonary fat embolism, pulmonary infarction, and pulmonary hemorrhage.⁶⁹ Acute management includes supportive care and oxygen, antibiotics to cover encapsulated and atypical organisms, bronchodilators, pain control, ventilatory support as needed, and transfusion. Incentive spirometry or continuous positive airway pressure can be helpful, especially in the perioperative setting. Hydroxyurea therapy and chronic transfusion therapy decrease the frequency of ACS, whereas inhaled NO attenuates the process acutely.^59,⁷⁰^–⁷² Airway reactivity is also common in children with sickle cell disease, in part due to NO deficiency, and it is responsive to bronchodilator therapy.^73,⁷⁴ In later life, children with sickle cell disease may develop restrictive lung disease and pulmonary hypertension as a result of repeated ACS-induced lung injury and chronic inflammation. NO deficiency, the result of decreased production, increased consumption, or altered metabolism, may also play an important role in these processes.^63,^68,⁷⁵

Infection is a common problem in this disease because of deficits in the immunologic system and the specific effects of splenic atrophy and dysfunction that occur over the first few years of life.⁵⁶ As a result of susceptibility to overwhelming infection by S. pneumoniae and H. influenzae type B, young children receive penicillin prophylaxis until 6 years of age and bacteria-specific immunizations. A host of infectious organisms have been implicated in ACS, and infection with gram-negative organisms (e.g., osteomyelitis caused by Salmonella) is common in older children and adults.⁶⁹

Stroke is a devastating complication that occurs in children with sickle cell disease. A history of overt strokes is elicited in 10% or more of these children, and silent strokes occur in another approximately 15%; one fourth of children are at risk for motor or cognitive deficits at the time of presentation for surgery.^76,⁷⁷ A child’s first stroke often appears as early as 2 to 5 years of age.^78,⁷⁹ Risk factors include a reduced hemoglobin concentration, increased concentration of HbS, increased leukocyte count, and a history of dactylitis. Strokes may be precipitated by pain episodes, ACS, and infection.⁸⁰ Children suffering an acute stroke are managed supportively with exchange transfusion to reduce the concentration of HbS to less than 30% and then chronic intermittent transfusions to minimize the risk of recurrence.⁸¹

The thrust of the current management of stroke is prevention. Based on the findings of the Stroke Prevention Trials (STOP 1 and 2), children are assessed annually by transcranial Doppler, and children with evidence of cerebrovascular compromise and some of those with magnetic resonance imaging abnormalities are managed with chronic transfusion therapy to minimize the risk of a stroke.⁸²^–⁸⁴

Renal abnormalities in sickle cell disease develop from repeated sludging episodes, which may cause thrombosis, progressive infarction, and necrosis of the renal medulla. Proteinuria, hematuria, hyposthenuria, renal tubular acidosis, and other clinical abnormalities occur. Acute and chronic renal failure may develop.^85,⁸⁶ Renal dialysis and transplantation have been successful therapeutic interventions for this population.⁸⁷

The clinical picture of sickle cell disease is altered to various degrees by concomitant qualitative and quantitative changes of hemoglobin. Sickle cell trait (HbAS) usually is benign, although it may be characterized by hematuria and hyposthenuria,^87,⁸⁸ and sickling may occur with HbAS under extremely altered physiologic circumstances (e.g., cardiopulmonary bypass).^89,⁹⁰ There is a small but significant risk of pulmonary emboli and sudden death with extreme exertion by individuals with HbAS, which has led to the mandatory offer of testing to all National Collegiate Athletic Association (NCAA) athletes.⁹¹

Children with HbSC disease usually have a greater baseline hemoglobin concentration and fewer complications than those with HbSS disease; delayed splenic autoinfarction reduces their risk for infection in early childhood.⁶² However, children with HbSC disease are more likely to have proliferative retinopathy and avascular necrosis of bone.⁵⁶

Children with HbSβ⁰ (i.e., one sickle globin allele and one thalassemic allele expressing no β-globin) have a course identical to that of HbSS, whereas those with HbSβ⁺ (i.e., one sickle globin allele and one thalassemic allele expressing β-globin at a reduced level) tend to have a more benign course that is proportional to the amount of normal β-globin expression. The coexistence of hemoglobin S with α-thalassemia produces a variable clinical picture, but it may predispose children to a greater incidence of pain episodes.⁶²

In addition to the treatment modalities mentioned earlier, many new and experimental modalities show promise in the treatment of sickle cell disease and its complications. They include induction of hemoglobin F by short-chain fatty acids such as butyrate or demethylating agents such as decitabine; membrane-active medications such as the Gardos channel inhibitors, magnesium; and antiadhesion therapies. New therapeutic targets are being identified, such a BCL11A, a zinc finger protein that plays a key role in the silencing of fetal globin genes. Reduction of BCL11A results in an induction of fetal globin.⁹² Hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative intervention for sickle cell disease when instituted before development of organ dysfunction, but its application is limited in part by the lack of suitable donors.^56,⁹³ To circumvent this limitation, gene therapy protocols using a child’s own stem cells have been approved for use.

Perioperative Considerations

Perioperative morbidity and mortality are greater in children with sickle cell disease than in the general population. These children often require surgical procedures; the most common are cholecystectomy ⁹⁴; ear, nose, and throat procedures⁹⁵; and orthopedic procedures (especially hip procedures for osteonecrosis).⁹⁶ Placement of long-term vascular access for transfusions, antibiotics, analgesia, and other therapies is frequently performed. The Cooperative Study of Sickle Cell Disease reported that 7% of all deaths among children with this disease were related to surgery.⁵⁴ Early reviews reported perioperative mortality rates as great as 10% and morbidity rates as great as 50% for children with sickle cell disease.⁹⁷^–¹⁰⁰ Studies published in the 1990s indicated that the 30-day mortality rate was about 1%.¹⁰¹ In a group of more than 600 patients managed according to standard guidelines of care and prospectively studied, the incidence of any complication was about 30%, and the incidences of ACS and pain crisis were 10% and 5%, respectively.⁶⁴ Patient factors (e.g., age, history of pulmonary disease, number of prior hospitalizations) and surgical factors (i.e., invasive or superficial) appear to affect the incidence of complications. The impact of newer interventions and technologies (e.g., laparoscopic and robotically assisted cholecystectomy and splenectomy)¹⁰²^–¹⁰⁴ on perioperative morbidity and mortality rates is unclear.

The principles of optimal perioperative care are based on maintaining optimal physiologic parameters throughout the perioperative period, avoiding factors that may precipitate a sickle crisis, optimizing pain management, and close consultation among hematologists, surgeons, and anesthesiologists (Table 9-9).¹⁰⁵ The child with sickle cell disease who is undergoing surgery should be viewed and managed primarily as a hematology patient whose care is being shared with, rather than assumed by, the surgeon and anesthesiologist during the perioperative period. Avoiding unnecessary and potentially dangerous surgical procedures (e.g., exploratory laparotomy to rule out appendicitis in a child who is experiencing an abdominal pain crisis) and minimizing perioperative complications should be the focus of the multidisciplinary care team. Based on a survey of perioperative management of sickle cell disease among anesthesiologists in North America, most anesthesiologists do consult with hematologists in all cases or on a case-by-case basis.¹⁰⁶

TABLE 9-9 Perioperative Concerns for Patients with Sickle Cell Disease

Preoperative Considerations

Screening if unknown status in at-risk children

Primary management by hematology service (in most circumstances)

History of acute chest syndrome, vaso-occlusive pain crises, hospitalizations, transfusions, transfusion reactions

Neurologic assessment (e.g., strokes, cognitive limitations)

History of analgesic and other medication use

Hematocrit

Oxygen saturation (on room air), chest radiograph

Pulmonary function tests (when appropriate)

Echocardiography (when appropriate)

Neurologic imaging (for recent changes)

Renal function studies

Transfusion crossmatch (e.g., antibody-matched, leukocyte reduced, sickle negative)

Transfusion to correct anemia (in most circumstances)

Parenteral hydration for nil per os (NPO) status

Pain management

Aggressive bronchodilator therapy

Appropriate antibiotic therapy, including presplenectomy antibiotics and immunizations (as indicated)

Intraoperative Considerations

Maintenance of oxygenation, perfusion, normal acid–basis status, temperature, hydration

Availability of appropriately prepared blood (as indicated)

Replacement of blood loss

Anesthetic technique appropriate for procedure and postoperative analgesic requirements

Attention to physiologic effects of laparoscopy on circulatory and respiratory function

Appropriate antibiotic therapy

Judicious use of tourniquets, cell saver, and cardiopulmonary bypass

Postoperative Considerations

Management by hematology service

Monitoring for complications, especially acute chest syndrome and vaso-occlusive pain crises

Maintenance of oxygen saturation monitoring and supplementation as needed, including supplemental oxygen the first 24 hours regardless of oxygen saturation

Appropriate hydration (oral plus parenteral)

Appropriate antibiotic therapy

Aggressive pain management

Early mobilization

Incentive spirometry (possibly with continuous or bilateral positive airway pressure) and bronchodilator therapy

Although there is no evidence to support or refute many of the long-standing guidelines for perioperative care and individual practices vary widely,¹⁰⁶ it seems appropriate to avoid the specific factors that may promote intravascular sickling: hypoxia, acidosis, hyperthermia, hypothermia, and dehydration.⁵⁵ Meticulous attention to pain management is also essential because perioperative vaso-occlusive pain is common and is associated with ACS. Monitoring of vital signs throughout the perioperative period is mandatory, especially monitoring of oxygenation with pulse oximetry. Oxygen saturation as determined by pulse oximetry may underestimate measured oxygen saturation in patients with sickle cell disease, although usually not to a clinically significant degree.^107,¹⁰⁸ Because ACS, a common (10%) and potentially life-threatening complication of surgery, occurs 1 to 3 days postoperatively, it is important to extend adherence to guidelines of care into the postoperative period, regardless of the apparent well-being of the child.⁶⁴ In light of the renal concentrating defect found in these patients, perioperative hydration is important to maintain and may require in-hospital preoperative care, although overhydration may compromise vulnerable cardiovascular and respiratory physiology.

Transfusion in the perioperative period remains a controversial subject.¹⁰⁹ Transfusion of non-HbS RBCs to a child with sickle cell disease has several beneficial effects: correction of anemia, dilution of HbS red cells, compensation for blood loss, and prevention of some complications (e.g., stroke). However, transfusion is not without risks, including alloimmunization,^34,¹¹⁰ transfusion reactions (about 7% in the perioperative period),⁶⁴ infection, iron overload, time, and expense. Although there have been many reports of surgery performed safely in children with sickle cell disease without preoperative transfusion,¹¹¹ uncontrolled studies indicate that preoperative transfusion does decrease the rate of perioperative complications.^94,¹⁰¹ The Preoperative Transfusion in Sickle Cell Disease Study Group demonstrated prospectively in 604 operations (70% were cholecystectomies and otolaryngologic and orthopedic operations) that simple transfusion (i.e., correction of preoperative anemia to 10 g/dL with straight transfusion) was as effective as aggressive transfusion (i.e., lowering the preoperative HbS level to less than 30%, often with exchange transfusion) in preventing perioperative complications and was associated with fewer transfusion-related complications in children.⁶⁴

To directly determine if transfusion prevents perioperative complications in the current era of surgical and anesthesia practices, an international randomized trial was initiated, the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) trial. However, this trial was halted in March 2011 due to an excessive number of complications in the nontransfusion group. Although the final results of TAPS have not been published, it remains prudent to follow prior recommendations for transfusion for moderate and complicated operations in sickle cell patients. It is currently recommended that most children with HbSS undergoing most surgical procedures receive preoperative correction of anemia with simple transfusion to a hemoglobin concentration of about 10 g/dL. Children maintained on chronic transfusion programs (e.g., stroke prevention) should continue such management preoperatively. Recommendations for children with HbSC disease are less clear because these children typically maintain a baseline hemoglobin concentration at about 10 g/dL. For HbSC children who have a history of ACS, frequent pain crises, underlying pulmonary disease, or other complications, it is recommended that they receive selective preoperative exchange transfusion to reduce the HbS concentration without increasing total hemoglobin.¹¹² Because of the high risk of alloimmunization in the sickle cell population, blood to be administered to these patients should undergo extended phenotype matching, including Rh, Cc, D, Ee, and Kell in addition to ABO^84,¹¹³; leukocyte reduction; and sickle cell screening. Directed donation of blood from family members should be avoided if the child is a hematopoietic stem cell transplant candidate because it can lead to alloimmunization and later graft rejection.

Anesthetic technique does not have a clear effect on perioperative outcomes for children with sickle cell disease.¹¹⁴ Inhalational anesthetics do not affect the sickling process, although there is some experimental evidence suggesting that halothane may increase the viscosity of sickled blood.¹¹⁵ Pharmacokinetics of some agents commonly used with general anesthesia such as atracurium may be altered in this population.¹¹⁶ Regional anesthesia has been associated with an increased risk of postoperative complications in one retrospective study,¹⁰¹ but it has not been shown to affect perioperative outcome in others.^94,⁹⁶ Vasodilatory and analgesic properties of regional anesthesia can be effective in the management of vaso-occlusive episodes and priapism and in providing perioperative anesthetic care.^117,¹¹⁸

Hyperventilation should be avoided because of its potential to reduce cerebral perfusion in children at an increased risk for stroke.¹¹⁹ The use of a tourniquet in HbSS and HbAS diseases has been questioned.¹²⁰^–¹²² However, tourniquets have been applied intraoperatively for up to 2 hours without complication, and the predominance of evidence supports their safe use as long as they are used carefully and selectively in combination with general guidelines of perioperative care (see Chapter 30).¹²³^–¹²⁶ Intraoperative blood salvage using cell saver devices has been used safely in sickle cell patients,¹²⁷ although there is some evidence that the salvage device itself may produce sickling in the processed blood, even sickle trait blood.¹²⁸ Cardiopulmonary bypass seems to be an optimal setting in which to induce sickling, given the cold, hypoxic, acidotic, and stagnant environment created. Although there are reports of bypass surgery conducted in children with HbSS or HbAS with standard bypass procedures without transfusion,¹²⁹^–¹³² these children usually are managed with aggressive exchange transfusion before or during bypass.

Thalassemias

Thalassemia disorders are among the most common genetic disorders worldwide, and they are characterized by a perturbation of the normal 1 : 1 ratio of α to β polypeptide chains, usually due to reduced synthesis of one polypeptide. The clinical severity of the disease in a child is a function of the degree of alteration of the synthetic ratio, ranging from an asymptomatic carrier state to chronic symptomatic hemolytic anemia to fetal death due to hydrops fetalis. α-Thalassemias commonly affect children of Southeast Asian descent and occur in those of African and Mediterranean descent. β-Thalassemias affect primarily children of Mediterranean, African, and Southeast Asian descent. Whereas state neonatal assays screening for HbS can often detect many forms of α-thalassemia, these tests can detect only profound forms of β-thalassemia because of the low levels of adult β chains present in the neonate. The concomitant presence of qualitatively abnormal hemoglobins (e.g., HbS, HbE) affects the clinical course of thalassemia disorders. The primary hemolytic anemia and the therapy used in the treatment of the disease may affect perioperative care.

Pathophysiology

Anemia in thalassemia is the result of hemolysis and ineffective erythropoiesis; the latter is the result of accelerated cell apoptosis triggered in part by excess deposition of unpaired globin chains in erythroid precursors.¹³³ Unpaired globin subunits are oxidized and form hemichromes, whose rate of formation determines rate of hemolysis. Precipitation of hemichromes leads to a complex process that includes release of toxic agents and formation of reactive oxygen species; alteration of red cell membranes, causing cells to become rigid, aggregate, and disintegrate; and activation of the coagulation process. As a result of chronic anemia and ineffective erythropoiesis, bone expansion and extramedullary hematopoiesis may develop in the liver and spleen, and marrow space expansion may occur at sites such as the cranium and paravertebral areas, thereby causing disfiguring bony changes.

Clinical and Laboratory Features and Treatment

The disease picture in α-thalassemia reflects complete loss of expression of one to four α-globin genes. As a four-gene globin deletion, it is characterized by hydrops and in utero or perinatal death unless diagnosed early and supported with in utero transfusions. As a three-gene deletion, or hemoglobin H (HbH) disease, it is relatively benign, characterized by chronic hemolytic anemia, which may be exacerbated by exposure to stress and oxidants.^134,¹³⁵ The few patients requiring intermittent transfusion therapy usually have a two-gene deletion along with a hemoglobin Constant Spring (HbCS) mutation. A two-gene deletion alone is characterized by mild, clinically insignificant microcytic anemia. A one-gene deletion is characterized by a silent carrier state with no anemia or microcytosis.

The clinical picture in β-thalassemia reflects partial or complete loss of expression of the β-globin genes. The broad spectrum of disease results from the number of genes affected and the degree to which each is affected. When only one β-globin gene is affected (i.e., β-thalassemia trait), mild microcytic anemia is the primary clinical manifestation. When both β-globin genes are affected, the clinical picture may be mild to moderate (i.e., thalassemia intermedia) or severe (i.e., thalassemia major or Cooley anemia), requiring chronic transfusions. Children with hemoglobin E (HgE)/β-thalassemia have symptoms ranging from very mild to severe, depending on the level of expression of the mutant β-globin gene.

The clinical problems in thalassemia are those associated with chronic anemia: the physiologic response to the need for increased erythropoiesis, transfusions to maintain a hemoglobin concentration greater than 9 g/dL, iron overload from excess transfusions and pardoxical increased iron absorption, and chelation therapy.¹³⁴ Clinical problems include transfusion-associated alloimmunization and infection, splenomegaly, bone abnormalities (due to extramedullary hematopoiesis, chelation therapy, and other factors), endocrine dysfunction (including hypogonadism, hypopituitarism, and diabetes mellitus), short stature, pulmonary hypertension, venous thrombosis and thromboembolism, and cardiomyopathy (primarily due to iron overload). Thalassemia patients may be hypercoagulable,¹³⁶ a condition that may be exaggerated after splenectomy.^136,¹³⁷

Routine therapies used to treat severe diseases and to prevent complications include phenotypic matching and leukocyte reduction of transfused blood, chelation therapy, and hormone and vitamin D therapy. When an appropriate donor is available, HSCT is recommended before severe liver damage occurs because it provides a potential cure for thalassemia. To ameliorate the course of the disease, other therapies are being investigated, including administration of erythropoietin, fetal hemoglobin modifiers (e.g., hydroxyurea, butyrate), and antioxidants. Gene therapy trials are ongoing, and at least one patient has become transfusion independent.¹³⁸

Perioperative Considerations

Children with moderate or severe thalassemia may require cholecystectomy, splenectomy, and vascular access placement for frequent transfusions.¹³⁹ Demineralized long bones may be prone to fracture, and older children may require osteotomies for bony deformities. Bony abnormalities of the maxillofacial area may render securing the airway challenging.¹⁴⁰ Laparoscopic and robotic techniques for cholecystectomy¹⁴¹ and splenectomy have been used successively in children with thalassemia, although perioperative hypertension may be a common problem in laparoscopic splenectomy.^142,¹⁴³ Open heart surgery requiring cardiopulmonary bypass with judicious use of sodium nitroprusside therapy has been successfully performed in a patient with HbH disease.¹⁴⁴ Perioperative considerations and concerns for children with thalassemia, especially for those with thalassemia major, are listed in Table 9-10.

TABLE 9-10 Perioperative Concerns for Patients with Thalassemia

Preoperative Considerations

Hemoglobin

Transfusion crossmatch if appropriate (antibody-matched, leukocyte-reduced source for frequently transfused children)

Evaluation for endocrine dysfunction (e.g., diabetes mellitus, hypopituitarism)

Cardiac function, including echocardiogram (when appropriate)

Hepatic function, awareness of risk of cirrhosis and iron or virus-induced damage

Airway evaluation

Presplenectomy antibiotics and immunizations (when appropriate)

Preparation for possible difficult airway

Intraoperative Considerations

Careful positioning of demineralized extremities

Attention to cardiovascular function, including postsplenectomy hypertension

Attention to physiologic effects of laparoscopy on circulatory and respiratory function

Prophylaxis for thromboembolism

Postoperative Considerations

Monitoring of cardiac function

Prophylaxis for thromboembolism

Thrombocytopenia

Platelet Disorders and Bleeding

Platelets are an essential component of hemostatic regulation. Platelets are distributed between the bloodstream (two thirds) and spleen (one third). Their normal life span is 7 to 10 days. In children, the platelet number may decrease due to decreased production or increased consumption, or they may have abnormal function. Bleeding typical of platelet disorders often involves skin and mucous membranes. Although there are many causes of primary and secondary thrombocytopenia in infants and children, this discussion focuses on idiopathic thrombocytopenic purpura (ITP).

Idiopathic Thrombocytopenic Purpura

ITP is the most common cause of acute-onset thrombocytopenia in the otherwise healthy child, and it commonly manifests in the operative setting. ITP has an estimated incidence of about 4 per 100,000 children, and it is usually a benign, self-limited disorder affecting children between the ages of 2 and 10 years.³⁵ Primary ITP has no clear predisposing cause, but secondary ITP is triggered by a drug or medical disorder. Diagnosis is by exclusion, the differential list is extensive, and response to ITP-specific treatment usually solidifies the diagnosis.

Pathophysiology

ITP is characterized by antibody-mediated clearance by tissue macrophages, resulting in thrombocytopenia (platelet count less tan 100,000/mm³) and shortened platelet survival. Antibodies may also suppress megakaryocytes and platelet development. Platelet autoantibodies may exist alone or as part of immune complexes, and they usually are immunoglobulin G (IgG) in type. They often show specificity for platelet membrane glycoproteins IIb-IIIa and Ib-IX.¹⁴⁵ Thrombocytopenia develops when the reticuloendothelial system, typically the spleen, destroys the antibody-covered platelets.

Clinical and Laboratory Features and Treatment

Typically, ITP in children is a benign process occurring after a viral illness or immunization that manifests as petechiae of mucosal surfaces or purpura over bony prominences, thrombocytopenia, and a normal to increased mean platelet volume with increased megakaryocytes in the marrow. This process resolves within weeks or months regardless of therapy. ITP is classified as newly diagnosed (less than 3 months), persistent (3 to 12 months), and chronic (more than 12 months).¹⁴⁶

Although platelet function in children with ITP is usually increased, treatment is often initiated only when the counts are less than 10,000 to 20,000/mm³.¹⁴⁵ Observation with avoidance of activity that may lead to head trauma is an increasingly accepted treatment plan. Medical treatment most commonly consists of agents that decrease monocyte/macrophage-mediated destruction of antibody-coated platelets (e.g., steroids, intravenous immunoglobulin, anti-D immunoglobulins, vinca alkaloids). Agents that decrease antibody production (e.g., cyclophosphamide, anti-CD20 antibody) and investigational agents that stimulate the thrombopoietin receptor are reserved for those who demonstrate an inadequate response to initial therapy.¹⁴⁷ Platelet transfusions are recommended only for life-threatening emergencies. Splenectomy removes a major site of platelet destruction and is recommended as an option only in chronic, symptomatic ITP or acute, life-threatening ITP unresponsive to medical treatment.^148,¹⁴⁹ This procedure, which is commonly performed noninvasively, has a success rate of about 75%.¹⁵⁰^–¹⁵²

Perioperative Considerations

In view of the clinical and laboratory features of ITP, the anesthesiologist providing care for the child with ITP who is undergoing splenectomy or incidental surgery should consider the concerns listed in Table 9-11. A hematologist should be consulted to assess the need for medical therapy, including platelet transfusion, before surgery.

TABLE 9-11 Perioperative Concerns for Patients with Idiopathic Thrombocytopenia Purpura

Preoperative Considerations

Hemoglobin, platelet count

History of platelet transfusions

History of corticosteroid use

History of infections

Presplenectomy antibiotic prophylaxis and immunizations (when appropriate)

Discussion with a hematologist regarding medical therapy and platelet transfusion for a platelet count <30,000/mm³

Discontinuation of any platelet-inhibiting medication (e.g., aspirin)

Intraoperative Considerations

Appropriate antibiotic coverage

Stress corticosteroid coverage

Medical therapy and platelet transfusion as above (platelets ideally administered after clamping of the splenic artery during splenectomy)

Judicious use of regional anesthesia, intramuscular medications, nasogastric tubes, nasal intubation, and other methods

Limited use of medications with potential bleeding risk (e.g., ketorolac)

Attention to physiologic effects of laparoscopy on circulatory and respiratory function

Postoperative Considerations

Hemoglobin, platelet count

Infection

Corticosteroid coverage

Pain management

Coagulation Disorders

Children may present for surgery with a personal or family history suggesting a bleeding disorder. The anesthesiologist must decide expeditiously whether to postpone surgery to further evaluate or treat the child. A careful medical history, physical examination, and family history, followed by laboratory evaluation in consultation with a hematologist, are important elements in screening for, diagnosing, and treating a bleeding disorder in the perioperative setting.

Screening

The clinical history of the child and family is the most essential screening tool. The family history should identify family members who have been labeled as bleeders, who have required blood transfusion unexpectedly during surgery, or who returned to surgery for unexpected postoperative bleeding. A history of maternal menorrhagia may also be significant. Suggestive signs and symptoms in a child’s medical history are easy bruising, mucosal bleeding, and in older girls, menorrhagia. Although diagnosing easy bruising is subjective, the clinician should suspect bleeding tendencies if skin bruising occurs in nontraumatized sites (e.g., trunk) or is unusually large without evidence of previous trauma. Mucosal bleeding includes epistaxis and gingival bleeding. Occasional nosebleeds can be common in children, but their clinical significance is enhanced by increased frequency, duration, bilaterality, and coexistence with abnormal bleeding from other sites. Gingival bleeding is common after tooth brushing or flossing, but its clinical significance is enhanced by spontaneous occurrence or chronicity, especially in the presence of good dental hygiene.¹⁵³ A history of prolonged or excessive bleeding is important when associated with umbilical dehiscence, dental work (especially extractions), and circumcision. Although mouth injuries can produce impressive blood loss acutely in any individual, recurrent or persistent bleeding from such an injury may indicate an underlying disorder.

Consultation with a hematologist and laboratory evaluation should be considered for children with a clinical history and physical examination result that suggest a bleeding diathesis, especially for children scheduled to undergo procedures associated with large blood loss or that make particular demands on hemostasis, such as tonsillectomy. Laboratory evaluation of all children, regardless of history or type of surgery, may result in false-positive results that lead to costly workups and potentially unnecessary cancellation of operations, both of which can contribute to greater health care inefficiencies and expense. Bleeding due to medications should be distinguished from an actual bleeding disorder.

When a bleeding disorder is strongly suspected, a set of laboratory tests that include a platelet count, PT, INR, aPTT, thrombin time (TT), and fibrinogen concentration should be ordered. The PT test is most sensitive to deficiencies in factors II, V, VII, and X, and it is useful for differentiating a vitamin K deficiency from other causes. The PT is most often used to monitor the anticoagulant effects of warfarin; it is not sensitive to the effects of heparin. The aPTT test is most sensitive to deficiencies in factors VIII, IX, and XI and less sensitive to deficiencies of factor V, factor X, prothrombin, and fibrinogen. The aPTT is also prolonged in deficiencies of the contact or kallikrein/kinin system proteins, factor XII, prekallikrein, and high-molecular-weight kininogen, but these deficiencies are not associated with bleeding. Because aPTT reagents vary in sensitivity for detection of deficiencies of each factor, it is inappropriate to make a general statement about the ability of this test to detect a specific abnormality; abnormal results require discussion with a hematologist or laboratory medicine physician. Although a prolonged aPTT may be caused by a deficiency in one or more factors, it can also result from inhibition by heparin or a plasma inhibitor, such as lupus anticoagulant. Correction of a prolonged aPTT after mixing the child’s plasma with normal plasma (1 : 1 mix) suggests a factor deficiency. The TT test, which determines the amount of time it takes for blood to clot, is useful for determining deficiencies or abnormalities in fibrinogen and is very sensitive to heparin contamination. Bleeding time, a thromboelastogram, and platelet function screens (e.g., PFA-100) are probably not appropriate as first-line screening tests.

Children with an upper limit of normal aPTT test result and a strongly suspicious personal or family history for a bleeding disorder may have an abnormality (e.g., von Willebrand disease). These children require further evaluation in consultation with a hematologist. Whether a procedure should be delayed for the consultation depends on several factors, including the patient’s history, site and urgency of surgery, potential bleeding risks associated with the planned procedure, and results of previously discussed set of screening tests.

Von Willebrand Disease

von Willebrand disease (vWD) is considered to be one of the most common bleeding disorders, although studies suggest that the prevalence may be as low as 1 case per 10,000 people.¹⁵⁴^–¹⁵⁷ Initially named pseudohemophilia because of an inheritance pattern that is different from that of hemophilia, vWD is the result of an abnormal amount, structure, or function of the vWF.¹⁵⁴

Pathophysiology and Classification

The glycoprotein vWF serves two main roles in the coagulation cascade: adhering platelets to damaged subendothelium and carrying factor VIII in plasma. vWF exists as small and large multimers. Large multimers play a more active role in the binding of platelets to subendothelium than do small ones and are therefore necessary for platelet adhesion, whereas binding to factor VIII is independent of multimer size. The two aspects of vWF make it an essential part of primary hemostasis (through platelet binding) and secondary hemostasis (as carrier of factor VIII to sites of injury).

Classification of vWD is essential for understanding and management of this disorder. The current classification was developed by a subcommittee on vWD through the International Society on Thrombosis and Haemostasis.^155,¹⁵⁶ The two general types are categorized as quantitative abnormalities (types 1 and 3) or qualitative abnormalities (type 2, including subtypes A, B, M, and N). All types are inherited in an autosomal dominant pattern, except types 2N and 3, which are autosomal recessive.

Because vWD is heterogeneous, clinical definitions have been proposed using categories such as mild, moderate, and severe, categories that are based on bleeding history (i.e., number of bleeding episodes) and laboratory measurement of factor concentration and activity.¹⁵⁷ As the molecular basis of vWD becomes better understood, classification of this disease likely will change to reflect the new data. For example, Rodeghiero and colleagues proposed a practical approach to diagnosing and categorizing patients with vWD to provide optimal management.¹⁵⁷ Their approach includes a standardized bleeding history score, focused laboratory analysis, and a trial infusion of DDAVP in certain subtypes. Categorization of patients with vWD is important for determining how they are managed in the perioperative setting.¹⁵⁸

Clinical and Laboratory Features and Treatment

Children with vWD may exhibit many of the clinical features associated with bleeding disorders in general, although there is a notable absence of joint bleeding. The typical symptoms of vWD reflect poor platelet adhesion and include bruising, epistaxis, and menorrhagia.

Children with vWD have traditionally been described as having prolonged bleeding times and aPTTs, but those with mild disease often have normal values. The aPTT is prolonged only if factor VIII activity is at or below a concentration that is determined by the sensitivity of the particular assay at an institution (often below 30% to 35%). The platelet functional assay (PFA-100) has better sensitivity and specificity (both near 90%) for diagnosis of the disease.^159,¹⁶⁰ The PFA-100 test, which measures closure time of an aperture on a membrane coated with collagen and adenosine diphosphate (ADP) or epinephrine, depends on vWF activity and platelet function. Because this test has some variability, its interpretation should be used in conjunction with results of other tests.¹⁶¹ Platelet count is typically normal in all types of vWD except type 2B.

Other laboratory tests used to delineate vWD include vWF antigen (vWF : A), which is a measure of the total level of vWF; vWF activity, often measured as a ristocetin cofactor activity (vWF : R), which is a measure of vWF binding to platelets through GPIb receptors; factor VIII coagulant activity; and vWF multimer analysis. Certain disease states have been associated with “acquired vWD” and include lymphoproliferative disorders or gammopathies (marked by antibodies to vWF), chronic renal failure, hypothyroidism, Wilms tumor, and certain congenital heart diseases, such as aortic stenosis (characterized by proteolysis of vWF multimers).¹⁵⁹

In consultation with a hematologist, determination of appropriate treatment based on specific diagnosis and response to therapy is necessary before surgery. Treatment focuses on increasing concentrations of endogenous vWF with administration of DDAVP when possible or on replacement of factors with factor concentrates.¹⁶² DDAVP is usually effective in type 1 but less so in types 2A and 2M. DDAVP may have little or even undesired effects in some children: it may increase abnormal vWF in types 2A, 2M, and 2N; it can exacerbate thrombocytopenia in type 2B; and its repeated administration may lead to tachyphylaxis. DDAVP usually is not administered to very young children because of the risk of free water retention, hyponatremia, and central nervous system pathology, including seizures. Similarly, intravenous fluids may need to be limited after its administration to any child. Factor concentrates (including factor VIII and vWF [Humate-P or Alphanate]) typically are required for types 2B, 2N, and 3. Cryoprecipitate may be used when vWF-containing concentrates are unavailable, but it is not recommended as first-line therapy because it is not virus free, and vWF in solvent or heat-treated cryoprecipitate may be abnormal.¹⁵³ Because of the complexity of response to therapies in this disease and the ever-changing availability of replacement products, determination of appropriate treatment in a particular child before surgery is crucial.^158,¹⁶³

Perioperative Concerns

The major preoperative concerns in children with confirmed vWD are directed toward appropriate preoperative treatment, avoidance of medications that may interfere with coagulation, and anticipation of intraoperative and postoperative bleeding (Table 9-12).^162,¹⁶⁴ All concerns should be addressed in consultation with a hematologist. Although regional anesthesia for these children usually is contraindicated, there are reports of its use without complications.¹⁶⁵

TABLE 9-12 Perioperative Considerations for Patients with von Willebrand Disease

Preoperative Considerations

Consultation with hematologist: establish correct diagnosis and response to desmopressin (DDAVP); administer DDAVP or viral attenuated factor concentrates containing factor VIII and von Willebrand factor (vWF) such as Humate-P for severe vWD or for those types not responsive to DDAVP ¹⁶¹

Determination of actual and desired factor concentrations and expected duration of postoperative therapy ¹⁶²

Discontinuation of any platelet-inhibiting medication (e.g., aspirin)

Intraoperative Considerations

Judicious use of regional anesthesia, intramuscular medications, nasogastric tubes, nasal intubation, and other procedures that may cause bleeding

Limited use of medications with potential bleeding risk (e.g., ketorolac)

Coagulation profiles, including platelet counts for more invasive surgeries

Treatment of bleeding with appropriate blood products

Consider use of antifibrinolytic agents (i.e., ε-aminocaproic acid, tranexamic acid)¹⁶³

Possible use of recombinant factor VIIa for severe bleeding episodes in severe vWD type 3 or patients with inhibitors

Postoperative Considerations

Follow factor concentrations (i.e., factor VIII and vWF)

Availability of blood products and factors

Appropriate treatment of bleeding episodes

Monitor for thromboembolism in children receiving multiple concentrates or antifibrinolytic agents, or both ¹⁶¹

Hemophilia

Hemophilia was first reported in the Talmud, in which there are descriptions of 8-day-old boys exsanguinating after ritual circumcision. Widespread public attention was drawn to this disease after members of Queen Victoria’s family developed sequelae from hemophilia in the late 19th and early 20th centuries. The discovery of multiple forms of hemophilia was first made in 1944 when blood from two hemophiliacs was mixed and found to clot. In 1952, hematologists explained their earlier finding by noting that a 10-year-old boy, Stephen Christmas, exhibited a type of hemophilia, factor IX deficiency, which differed from the classic form, factor VIII deficiency.

Hemophilia is a group of congenital bleeding disorders caused by deficiency in factor VIII (i.e., hemophilia A, or classic hemophilia), factor IX (i.e., hemophilia B, or Christmas disease), or factor XI (i.e., hemophilia C). During the 10-year period from 1982 through 1991, the incidence of the more common varieties, hemophilia A and B, was 1 case per 5032 live male births in the United States within a six-state surveillance area; the prevalence of hemophilia A was 10.5 cases per 100,000 male births, and that of hemophilia B was 2.9 cases per 100,000 male births.¹⁶⁶

Because of X-linked recessive inheritance of hemophilia A and B, family history is very important in establishing the diagnosis. Although boys are usually affected, girls may rarely inherit the disorder if their fathers are affected and their mothers are carriers or in instances of extreme lyonization (inactivation of an X chromosome). The daughter of an affected father is an obligate carrier with a 50% chance of passing it on to any of her sons. De novo mutations are relatively common and suspected in male patients lacking a family history.¹⁵⁹ Hemophilia C is a mild form of hemophilia, affecting primarily Ashkenazi Jews. It is distinguished from the other two forms of hemophilia by an autosomal recessive inheritance pattern (linked through chromosome 4), lack of joint bleeding, and infrequent need for treatment. Affected female patients may notice heavy menses, and affected male patients may have frequent nosebleeds and occasionally have excessive bleeding during surgery.

Pathophysiology

Normal in vivo hemostasis initiates at sites of endothelial disruption through interaction of activated factor VII (FVIIa) and tissue factor (TF) to form a complex that activates factor IX and factor X directly. Activated factor IX in conjunction with factor VIII further activates factor X, which with factor V converts prothrombin to thrombin. Both factor VIII and factor IX are required for sufficient hemostasis, as evidenced by the severe bleeding that occurs if either is completely deficient. Factor XI activates factor IX, but its precise role in the hemostatic pathway is not completely understood.

Clinical and Laboratory Features and Treatment

The wide range of clinical features is similar for hemophilia A and B (Table 9-13). The severity of bleeding in these children directly relates to the degree of their deficiency.¹⁵⁹ Children with mild or moderate hemophilia may bleed excessively only after a hemostatic challenge such as trauma or surgery, whereas children with severe hemophilia may bleed spontaneously (e.g., hemarthroses).¹⁶⁷ Female carriers on average have 50% of normal factor concentrations and usually are asymptomatic, although they occasionally present with a clinical picture similar to that of mild cases of hemophilia.¹⁵⁹

TABLE 9-13 Clinical Manifestations of Hemophilia A

Results of a general coagulation screen are typically normal except for the aPTT, which is prolonged in proportion to the concentration of factors in the blood. The diagnosis is confirmed by measuring the specific factor concentrations.¹⁶⁸ If hemophilia is suspected but there is no family history, testing for vWD is prudent, especially for the types that may mimic hemophilia (i.e., types 2N and 3). Because of the variable sensitivity of the aPTT to specific factor deficiencies, the ability of this test to detect carriers varies between laboratories; diagnosis of a carrier state usually requires specific factor assays.

Hemophilias A and B are treated by replacing the deficient factor concentrations. These factor concentrations should be maintained at specified levels to prevent sequelae (Table 9-14). Exposure to plasma products should be minimized. The duration of treatment should be tailored to the severity of disease. DDAVP may be effective in selected mild cases by increasing factor VIII concentrations through the release of endogenous stores. Because tachyphylaxis limits the prolonged use of DDAVP, it is typically recommended only for minor operations.¹⁶⁷ For most cases, especially for those who require increased factor concentrations to be maintained for effective hemostasis, factor concentrates should be used. Although recombinant forms are preferable because they do not carry infectious risk, substitution with plasma-derived forms may be needed when supplies are limited.^159,¹⁶⁷ For the rare patient with hemophilia C who has excessive surgical bleeding, treatment with recombinant factor XI or FFP may be required. It is essential to consult with a hematologist to determine a customized factor treatment plan for every child with hemophilia.

TABLE 9-14 Treatment Targets for Hemophilia A and B

Bleeding Site	Target Concentrations for Factor VIII or IX (%)	Duration of Treatment (days)*
Muscle	30-50	1-2
Joint	50-80	1-2
Gastrointestinal tract	40-60	10-14
Oral mucosa	30-50	2-3
Epistaxis	30-50	2-3
Hematuria	30-100	1-2
Retroperitoneal	80-100	7-10
Central nervous system	80-100	14
Trauma or surgery	80-100	14

^*May be reduced depending on clinical circumstances and severity of disease.

Modified from Brown DL. Congenital bleeding disorders. Curr Probl Pediatr Adolesc Health Care 2005;35:38-62.

Children who have developed inhibitors to factor concentrates pose a challenge in the perioperative period. Until recently, they were denied surgery unless it was absolutely necessary, at which point they were often managed with increased concentrations of factors or a desensitization regimen. However, a review that included two randomized, controlled trials and data from the Hemophilia Research Society and the Hemophilia and Thrombosis Research Society reported effectiveness of recombinant factor VIIa (rFVIIa) for most of these patients.¹⁶⁹ Among the randomized trials, one study compared two bolus-dosing regimens (35 versus 90 µg/kg), and the other study compared bolus dosing with continuous infusion; the greater dosing regimen was more effective for major operations. Combining data from these studies and the two Research Society databases, the overall effectiveness rate of rFVIIa in controlling bleeding approached 84%, with a low thrombotic rate of less than 1%. Such evidence is providing more options for these difficult-to-manage patients with inhibitors. Alternatively, partially activated prothrombin complex concentrates, such as factor VIII inhibitor bypass activity (FEIBA, Baxter Healthcare Corp., Westlake Village, Calif.), have been effective for patients with inhibitors undergoing surgery.¹⁷⁰

Perioperative Concerns

The perioperative concerns in hemophilia focus on prevention and treatment of bleeding, similar to the management of patients with vWD (Table 9-15). Many consider regional anesthesia to be contraindicated for patients with hemophilia, but there are reports of its use without complications as long as factor concentrations are maintained.¹⁷¹

TABLE 9-15 Perioperative Concerns for Patients with Hemophilia

Preoperative Considerations

Consultation with hematologist, establishment of correct diagnosis

Determination and testing of treatment plan, including use of desmopressin or factors (concentrates or recombinant)

Consideration of multiple procedures performed together to reduce factor exposure

Discontinuation of any platelet-inhibiting medication (e.g., aspirin)

Intraoperative Considerations

Judicious use of regional anesthesia, intramuscular medications, nasogastric tubes, nasal intubation, and other procedures that may cause bleeding

Limited use of medications with potential bleeding risk (e.g., ketorolac)

Follow coagulation profiles, especially factor levels (factors VIII and IX)

Anticipate and treat bleeding with appropriate blood products

Consider recombinant activated factor VII (rFVIIa) for severe bleeding

Postoperative Considerations

Maintain factor concentrations for specified time period as recommended by the hematologist

Ensure availability of blood products and factors from the blood bank

Anticipate and treat bleeding episodes

Hypercoagulability

A hypercoagulable state is a condition in which the development of thrombus is favored (i.e., thrombophilia). The condition results in an increased risk for abnormal clot formation and venous thromboembolic events (VTEs), which often are the presenting symptoms at the time of diagnosis. Thrombophilia can be acquired or congenital. The incidence of VTE among children is less than it is among adults, even in those with known congenital thrombophilic conditions,¹⁷² although neonates and adolescents are at relatively high risk in the pediatric population.¹⁷³ Congenital thrombophilic conditions include factor V Leiden disorder, prothrombin gene mutation, protein C and S deficiencies, and antithrombin III deficiency.¹⁷⁴ Risk factors for acquired thrombophilia include the presence of a central venous catheter, infection, malignancy, surgery, or trauma.¹⁷³

Screening of nonoperative children with suspected hypercoagulability is controversial and not recommended for those who are asymptomatic, even those with a positive family history.¹⁷² Evidenced-based guidelines for children are lacking with regard to screening and prophylactic treatment of those with suspected hypercoagulability. Current evidence suggests pharmacologic prophylaxis in the nonoperative setting is recommended only in children on long-term home total parenteral nutrition (TPN) and those with specific complex cardiac lesions (e.g., Fontan patients).¹⁷⁵ However, children who present for surgery with a strong family history of thromboses may benefit from screening and referral to a hematologist for management and consideration of pharmacologic prophylaxis, such as enoxaparin administered postoperatively. The use of nonpharmacologic prophylaxis, including early mobilization after surgery, adequate hydration, and compression stockings, is left to the discretion of individual providers and to institutional practice based on the child’s medical history, family history, and risk factors for VTE.

Cancer and Hematopoietic Stem Cell Transplantation

Cancer

Cancer is the second and fourth most common cause of death in children younger than 15 and 20 years of age, respectively.^176,¹⁷⁷ The most common malignancies affecting children are different from those affecting adults, and they include leukemia, brain tumors, lymphomas, and solid tumors such as sarcomas of soft tissue and bone. Embryonal tumors (e.g., neuroblastoma, Wilms tumor, retinoblastoma, medulloblastoma) are unique to early childhood. Survival rates for most pediatric cancers have improved significantly in the past several decades; more than 80% of children diagnosed with a childhood malignancy will become 5-year survivors of their cancers.^178,¹⁷⁹ The great improvements in survival for many malignancies of childhood are directly related to advances in diagnostic modalities and the large percentage of children treated on cooperative clinical trial protocols. Treatment follows these protocols and may include chemotherapy, radiation therapy, biologic modifiers, and HSCT.

Children with cancer typically undergo many surgical procedures that require anesthesia. The procedures may occur before the initiation of cancer therapy, during therapy, years into remission, or during terminal stages of the disease. Certain considerations apply to this population, including the direct effects of the tumor, effects of chemotherapy and radiation therapy, impact of the surgical procedure, pain syndromes, and psychologic vulnerabilities of the child and family. Survivors of childhood cancer experience various long-term sequelae after completion of cancer therapy. Although the broad field of pediatric oncology is beyond the scope of this discussion, some commonalities relating to perioperative care are described.

Clinical and Laboratory Features and Treatment

The direct effects of tumor, even at the time of diagnosis, may contribute to morbidity and mortality. For example, a childhood tumor may manifest with increased intracranial pressure, pleural or pericardial effusion, or compression of abdominal organs. Lymphoma often manifests with symptoms associated with an anterior mediastinal mass, including respiratory distress and cardiorespiratory collapse under anesthesia.^180,¹⁸¹ Most children with Hodgkin disease or non-Hodgkin lymphoma have mediastinal involvement at diagnosis, and almost one half have respiratory symptoms at presentation (see Chapter 13).^182,¹⁸³

Myelosuppression, which manifests with various degrees of anemia, thrombocytopenia, and neutropenia, is a common direct effect of cancer in children. Anemia is common at the time of diagnosis of many pediatric cancers, including 50% to 75% of children with newly diagnosed neuroblastoma, rhabdomyosarcoma, Hodgkin disease, Ewing sarcoma, and osteosarcoma ¹⁸⁴ and 80% of children with acute lymphoblastic leukemia (ALL).¹⁸⁵ Thrombocytopenia is typically identified during the diagnosis of children with acute leukemia and is common with tumors causing bone marrow infiltration.^186,¹⁸⁷ Neutropenia is usual in children with ALL. Hyperleukocytosis is predominant in children with acute myelogenous leukemia (AML), 20% of whom present with a white blood cell count greater than 100,000/mm³.^185,¹⁸⁸ This high concentration of leukemic blasts, especially when the count is greater than 200,000/mm³, may lead to intravascular clumping and the potentially fatal condition of leukostasis.¹⁸⁹ Myelosuppression may be a direct effect of tumor cells and marrow infiltration by tumor cells and may result from radiation therapy and chemotherapy. As a consequence of myelosuppression, children with cancer have a frequent need for transfusion of blood products and are at risk for procedure-acquired and line-related infections and for delayed wound healing after surgical procedures. Frequent hospitalizations and immune compromise predispose them to colonization and infection by nosocomial, community-acquired, antibiotic-resistant organisms and opportunistic infections. Neutropenia predisposes them to specific infections such as perirectal abscesses and typhlitis.

An uncommon but potentially fatal effect of the tumor itself is tumor lysis syndrome (TLS). TLS is most common with certain hematologic malignancies, especially ALL and Burkitt lymphoma, but it also occurs with other malignancies characterized by a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic therapy. TLS is characterized by rapid and massive destruction of tumor cells and resultant massive release of phosphorus, potassium, nucleic acids, and proteins that is sufficient to cause metabolic derangements and possible renal failure and death.^190,¹⁹¹ TLS can occur spontaneously, especially in children with AML, but it more often manifests in the setting of cytotoxic therapy, radiation therapy, fever, surgery, and anesthesia.¹⁹²^–¹⁹⁷

Chemotherapy used in pediatric oncology leads to myelosuppression and to a host of important side effects that may be clinically important in the perioperative setting (Table 9-16). These effects of chemotherapy can be synergistic with toxicities of radiation therapy.¹⁹⁸ New chemotherapeutic agents are continuously being introduced, and at academic centers, the use of investigational agents is common. Although it is impossible to provide a comprehensive review of chemotherapeutics, the most common agents that cause toxicities of particular importance to the delivery of anesthesia are briefly mentioned here, and a complete list of toxicities can be found in E-Table 9-1.

TABLE 9-16 Therapy-Related Side Effects and Toxicity

Drug	Side Effects
l-Asparaginase	Hyperglycemia, hypersensitivity, hepatic dysfunction (secondary hypoalbuminemia and coagulopathies), pancreatitis, thrombosis, stroke
Bischloroethyl nitrosourea (BCNU)	Encephalopathy, hepatotoxicity, pulmonary toxicity
Bleomycin	Anaphylactoid reactions, fever, hyperpigmentation, nausea, vomiting, pulmonary fibrosis
Busulfan	Encephalopathy, hepatotoxicity, pulmonary toxicity
Carboplatin	Myelosuppression, nausea, vomiting, nephrotoxicity, neurotoxicity, ototoxicity
Cisplatin	Nausea/vomiting, nephrotoxicity, ototoxicity, peripheral neuropathy
Corticosteroids	Adrenal suppression, avascular necrosis, cataracts, edema, gastritis, hyperglycemia, hypertension, myopathy, osteoporosis, obesity, osteopenia, psychosis
Cyclophosphamide (Cytoxan)	Cardiotoxicity, hemorrhagic cystitis, myelosuppression, nausea, vomiting, syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Cyclosporine	Cortical blindness, electrolyte disturbances, encephalopathy, gingival hyperplasia, hemolytic uremia, hepatotoxicity, hyperlipidemia, hypertension, hirsutism, myositis, paresthesias, tremor
Cytarabine	Myelosuppression, mucositis, hepatitis, nausea/vomiting, neurotoxicity
Dactinomycin (Actinomycin D)	Nausea/vomiting, mucositis, myelosuppression, radiation recall
Daunorubicin (Daunomycin) Doxorubicin (Adriamycin) Idarubicin (Idamycin)	Cardiomyopathy, mucositis, myelosuppression, red-orange urine
Etoposide	Hypotension, mucositis, myelosuppression, nausea, vomiting
Ifosfamide	Hemorrhagic cystitis, myelosuppression, nephrotoxicity, neurotoxicity
Melphalan	Mucositis
Methotrexate	Hepatotoxicity, mucositis, myelosuppression, renal failure, neurotoxicity
Mercaptopurine (6-MP)	Hepatotoxicity, myelosuppression
Mycophenolate mofetil (Cellcept)	Electrolyte disturbance, gastrointestinal toxicity, hypercholesterolemia, myelosuppression, rash
Procarbazine	Myelosuppression
Sirolimus	Hyperlipidemia, myelosuppression
Tacrolimus (Prograf)	Anemia, anorexia, back pain, encephalopathy, diarrhea, hyperglycemia, nephrotoxicity, pleural effusion, rash
Thiotepa	Neurotoxicity, mucositis
Thioguanine (6-TG)	Hepatotoxicity, myelosuppression
Total body irradiation	Dental/bony maldevelopment, gastrointestinal toxicity, hepatotoxicity, pulmonary toxicity
Vinblastine (Velban)	Myelosuppression, neurotoxicity, SIADH
Vincristine (Oncovin)	Neurotoxicity, SIADH

Modified from Carpenter PA, Mielcarek M, Woolfrey AE. Hematopoietic cell transplantation. In: Irwin S, Rippe JM, editors. Intensive care medicine. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 2150-68.

E-TABLE 9-1 Organ Toxicity of Chemotherapeutic Agents

Corticosteroids are frequently used and may cause adrenal suppression, hypertension, thromboembolism, and obesity; the latter potentially renders venous access and tracheal intubation difficult. Children who have received corticosteroid therapy have a period of measurable glucocorticoid-induced adrenal suppression of 2 weeks to 8 months after such therapy.¹⁹⁹^–²⁰⁵ Because of this variability, administering stress-dose steroids in the first 1 to 2 months after cessation of glucocorticoids is reasonable.¹⁹⁹ However, any child at risk of TLS should not receive corticosteroids without direct discussion with an oncologist.

The anthracycline drugs (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin) and mitoxantrone cause cardiomyopathy in a dose-dependent fashion, which is aggravated by radiation delivered to the precordial area. About 10% of children who received a cumulative dose of 300 mg/m² or more of anthracycline develop clinically significant cardiomyopathy.²⁰⁶ Later studies demonstrated clinically significant cardiomyopathy after much smaller doses^207,²⁰⁸ and an increased sensitivity in children with trisomy 21 and leukemia.²⁰⁹ Children receiving anthracyclines should be evaluated with echocardiography at baseline and intermittently during the course of therapy and for a prolonged period after therapy because anthracycline-induced cardiac failure can take years to fully declare itself.^210,²¹¹ Physical examination may miss more than 50% of children with heart failure.²¹² A recent echocardiogram should be available preoperatively if a child has received anthracycline therapy and any of the following conditions are met: cumulative dose greater than 240 mg/m², any dose received during infancy, or chest irradiation dose greater than 30 Gy with concomitant anthracycline treatment.^213,²¹⁴ Although uncommon, radionuclide angiocardiography may be chosen for those with poor echocardiographic windows.^210,²¹⁵

Several other chemotherapeutic agents are of interest to the anesthesiologist caring for a child with cancer. l-Asparaginase is associated with a 1% to 2% risk of hemorrhage or thrombosis due to deficiencies in fibrinogen, plasminogen, antithrombin III, and vWF,²¹⁶^–²¹⁸ as well as hepatic dysfunction and acute hemorrhagic pancreatitis. Bleomycin can produce acute pneumonitis and progression to pulmonary fibrosis. Although the incidence and risk in children are not known, reports suggest that 46% of adults treated with cumulative doses greater than 400 units/m² develop bleomycin-induced pneumonitis and 3% of these die.²¹⁹^–²²¹ Studies suggest that high concentrations of inspired oxygen during or soon after bleomycin treatment may promote pulmonary toxicity and lead to postoperative respiratory distress.²²²^–²²⁴ A medical history and physical examination are sufficient to determine whether pulmonary function testing is required preoperatively.²²⁵^–²²⁷ Cisplatin and ifosfamide may cause renal tubular damage that can lead to Fanconi syndrome with electrolyte wasting. Methotrexate may cause renal failure at large doses (more than 1 mg/m²). Vinblastine and vincristine may cause peripheral neuropathies and seizures. Increasingly, biologic mediators such as retinoids are being used to modify tumor biology, and recombinant antibodies are used to directly attack tumors and modulate the immune response to tumors. The use of investigational agents and novel chemotherapeutics amplifies the importance of reviewing cases with the oncologist.

Toxicity from the effects of radiation therapy to healthy tissues is unavoidable, and the developing tissues of children are particularly susceptible to the acute and late effects of irradiation. The susceptibility of normal tissues depends on the total and fractional dose received, the sensitivity of the tissue to the dose of radiation, the volume of tissue irradiated, and time course of treatment (Table 9-17). Concurrent chemotherapy potentiates toxicity.

TABLE 9-17 Late Effects of Radiation Therapy

Radiation Field	Late Effects	Risk Factors
Cranial	Neurocognitive deficits	>18 Gy, IV/IT methotrexate
	Leukoencephalopathy	>18 Gy with IT methotrexate
	Growth hormone deficiency	>18 Gy
	Panhypopituitarism	>40 Gy
	Large vessel stroke	>60 Gy
	Second cancers	Variable
	Dental problems	>10 Gy
	Cataracts	>2-8 Gy single dose, 10-15 Gy fractionated dose
	Ototoxicity	>35-50 Gy
Chest	Cardiac disease
	Coronary artery disease	>30 Gy
	Cardiomyopathy	>35 Gy, >25 Gy with anthracyclines
	Valvular disease	>40 Gy
	Pericardial disease	>35 Gy
	Arrhythmias	Unknown
	Thyroid disease
	Hypothyroidism	>20 Gy local, >7.5 Gy TBI
	Hyperthyroidism	>20 Gy local, >7.5 Gy TBI
	Thyroid nodules, cancer	Any dose
	Pulmonary disease
	Pulmonary fibrosis	>15-20 Gy
	Restrictive lung disease	Unknown
	Obstructive lung disease	Unknown
Abdomen/pelvis	Chronic enteritis	>40 Gy
	Gastrointestinal malignancy	Unknown
	Hepatic fibrosis/cirrhosis	>30 Gy
	Renal insufficiency	>20 Gy
	Bladder disease
	Fibrosis	>30 Gy prepubertal, >50 postpubertal
	Hemorrhagic cystitis	Enhances cyclophosphamide and ifosfamide effect
	Bladder cancer	Unknown
	Gonadal dysfunction
	Ovarian failure	4-12 Gy
	Testicular failure	>1-6 Gy
Any radiation	Skin cancer
	Musculoskeletal changes
	Bone length discrepancy	>20 Gy
	Pathologic fractures	>40 Gy
TBI	All the above

Gy, Gray; IT, intrathecal; IV, intravenous; TBI, total body irradiation.

From Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient—part 1: a review of antitumor therapy. Pediatr Anesth 2010;20:295-304.

Almost every organ system is affected by cancer and its treatment. Nausea and vomiting are common. Nutrition is often compromised, along with skin integrity and bone and tooth mineralization. Mucositis can lead to difficult intubation because of pseudomembrane formation, supraglottic edema, and bleeding from the friable oral mucosa.^228,²²⁹ Acute and chronic pain often require complex treatment regimens that may include opioids, nonsteroidal antiinflammatory agents, antidepressants, anxiolytics, and a wide range of complementary and alternative modalities.

Perioperative Considerations

A retrospective review of 177 children undergoing 3833 radiotherapy sessions with anesthesia reported a complication rate of 1.3%, which is comparable to that for children without cancer anesthetized with propofol.²³⁰ However, it is clear that many children with cancer who present to the operating room are gravely ill and susceptible to relatively small changes to their physiology.

All of the described considerations regarding the possible effects of pediatric cancer and its treatment may influence our strategies in the perioperative period. Children with cancer undergo a host of procedures that require anesthesia during acute and chronic phases of disease. Included among them are diagnostic tumor or lymph node biopsy; tumor resection; placement of peripheral and central venous access for treatment and nutrition; diagnostic and monitoring procedures (e.g., lumbar puncture, bone marrow aspirate and biopsy, lung and liver biopsy, skin biopsy, bronchoalveolar lavage, esophagogastroduodenoscopy); radiologic procedures (e.g., magnetic resonance imaging, computed tomography, nuclear scans, positron emission tomography); radiation therapy; and placement of pain management devices (e.g., indwelling epidural catheters). Splenectomy is performed as part of staging or management of some pediatric malignancies, and the procedure may be associated with increased risk of postoperative infection, postoperative thrombocytosis, and thrombocytopenia.²³¹

Surgical intervention may be required for acute and potentially life-threatening emergencies in children with cancer, and the effects of specific tumors can complicate anesthesia care. Wilms tumor may be accompanied by an acquired vWD condition, and anterior mediastinal masses may produce superior vena cava obstruction, pulmonary artery compression, and tracheal obstruction.^181,¹⁸² Neuroblastoma may be accompanied by pheochromocytoma-like signs and symptoms (3% of cases),²³² and in advanced stages, it may cause massive hepatic enlargement. Spinal tumors may cause acute spinal cord compression, and tumor or hemorrhage in the brain may cause acute intracranial hypertension. In view of the complexity of pediatric oncologic disease, there are many considerations for the perioperative period,²³³ as detailed in Table 9-18.

TABLE 9-18 Perioperative Concerns in Pediatric Cancer and Hematopoietic Stem Cell Transplantation

Preoperative Considerations

Intraoperative Considerations

Postoperative Considerations

Patient-appropriate opioid and other analgesic administration

Sterile technique with central line access

Observation of indicated isolation precautions

Hematopoietic Stem Cell Transplantation

The first attempts to use bone marrow clinically to treat malignancy took place about 50 years ago.²³⁴ HSCT is a potentially curative treatment for a wide range of malignant and nonmalignant pediatric disorders. Throughout the process of HSCT, children are likely to undergo procedures that require anesthesia.

HSCT is used in the treatment of leukemia, lymphoma, solid tumors (e.g., neuroblastoma), myelodysplasia, aplastic anemia, hemoglobinopathies (including sickle cell disease and thalassemia), and congenital immune and metabolism deficiencies.^235,²³⁶ Hematopoietic stem cells used in the transplantation can be obtained from bone marrow, “mobilized” peripheral blood, or umbilical cord blood. The source of the cells may be the child (autologous), an identical twin (syngeneic), or another individual (allogeneic). Allogeneic donor cells are commonly derived from HLA-identical siblings (available in about 30% of patients), but advances in matching and supportive care have improved outcomes with HLA-matched unrelated and mismatched donors.^237,²³⁸ Accumulative toxicity in HSCT derives from the underlying illness and complications of past therapy, the transplant-conditioning regimen, complications resulting from long-term myelosuppression, and graft-versus-host disease and its treatment.

Clinical and Laboratory Features and Treatment

The process of HSCT involves several steps:

1. The preparative or conditioning regimen, during which high-dose chemotherapy with or without irradiation or immunomodulating agents eradicates malignancy (where present), clears marrow space for incoming stem cells, and suppresses the recipient’s immune system

2. Transplantation through infusion of hematopoietic stem cells

3. Transplant engraftment (more than 30 days after transplantation)

4. Early engraftment (30 to 100 days after transplantation)

5. Late engraftment (more than 100 days after transplantation)

Side effects and toxicities of therapeutic modalities can affect the transplant recipient throughout the process (see Tables 9-16 and 9-17). The incidence of transplantation-related morbidity and mortality depends on the patient’s age, primary disease, comorbidities, and histocompatibility between donor and recipient. Complications contributing to morbidity and mortality are related to infection, regimen-related toxicity, and alloreactivity.²³⁹

Immunologic and physical host defenses are impaired throughout the transplantation process. Children are vulnerable to a wide range of routine and opportunistic pathogens, including bacteria, fungi, and viruses.

Regimen-related toxicity can involve every organ of the body through the direct and indirect effects of irradiation and chemotherapy (see Tables 9-16 and 9-17 and E-Table 9-1). Mucositis is common and can increase the risk of aspiration and airway compromise.^229,²⁴⁰ Sinusoidal obstruction syndrome (SOS), previously called veno-occlusive disease, occurs in 10% to 40% of children after HSCT. Mortality rates range from 19% to almost 50% due to hepatorenal failure and subsequent multiple-organ failure. SOS is characterized by hepatomegaly, jaundice, and fluid retention; its presence requires careful attention to fluid balance because sodium administration must be minimized, and coagulation abnormalities and refractoriness to platelet transfusions may occur.²⁴¹^–²⁴³ Other gastrointestinal complications include hemorrhage,²⁴⁴ infection, and opioid-induced abdominal pain and distention (i.e., narcotic bowel syndrome). Acute pulmonary complications occur in 30% to 60% of HSCT patients and include infection, hemorrhage, edema, bronchiolitis obliterans, acute respiratory distress syndrome (ARDS), and idiopathic pneumonia syndrome (IPS), a noninfectious inflammatory lung process.²⁴⁵^–²⁴⁷

In the early phase after HSCT, significant cardiomyopathy and arrhythmias are uncommon (5%), but sepsis, cardiovascular collapse, and heart failure are common admitting diagnoses of the 10% to 40% of children who require intensive care after HSCT.²⁴⁷^–²⁵⁰ Late cardiac complications depend on the dosage of radiation and cardiotoxic chemotherapeutics used during the conditioning regimen. Acute renal failure occurs in 30% to 50% of children^251,²⁵² and warrants judicious use of fluids in these patients²⁵³; hemorrhagic cystitis is also common.²⁵⁴ A process of thrombotic microangiopathy similar to hemolytic uremic syndrome may occur in one fourth of children receiving cyclosporine or the calcineurin inhibitor tacrolimus.²⁵⁵ Central nervous system complications include infection, hemorrhage, and encephalopathy and peripheral neuropathy due to metabolic and chemotherapeutic effects.²⁵⁶^–²⁶⁰

Graft-versus-host disease (GVHD) is the clinical manifestation of the recognition of recipient alloantigens by donor T cells. Acute GVHD is a common event (incidence depends on the histocompatibility of the donor and recipient) before day 100 after transplantation, and it is characterized by inflammatory dermatitis, enteritis, and hepatitis. Chronic GVHD occurs in 6% to 50% of pediatric patients and is typically recognized 100 days or more after transplantation. This broad range of incidence depends on the age of donor and recipient, gender matching, and degree of matching between donor and recipient.²⁶¹ Chronic GVHD has many features of autoimmune diseases (e.g., sclerodermatous changes, dry mouth and conjunctivae, esophagitis, pulmonary dysfunction including bronchiolitis obliterans, contractures of extremities and soft tissue, alopecia, thrombocytopenia). Opportunistic infections are common during chronic GVHD. Hemolysis is an additional manifestation of alloantigenicity, the result of major and minor blood group incompatibilities between donor and recipient.

In contrast to the myeloablative procedures described previously in the context of malignant disorders, nonablative transplants are increasingly being used, particularly in nonmalignant disorders. Use of these transplants is based on the observation that in some instances, minimal myelotoxicity in conjunction with profound and prolonged immunosuppression leads to successful donor engraftment.²⁶² This modality is mostly used in children with nonmalignant hematologic conditions, marrow failure, and immunodeficiency syndromes.

Perioperative Considerations

Surgical and procedural interventions are common throughout the transplantation process and are similar to those described earlier for children with cancer. A surgical procedure that is an integral component of HSCT is harvesting of hematopoietic stem cells from the recipient or another individual. Harvesting of bone marrow in children usually requires general anesthesia, although the procedure can be performed under spinal anesthesia with equivalent safety.²⁶³ The donor is usually placed in a prone position to extract approximately 10 mL/kg (recipient weight) of marrow from the posterior iliac crests. When stem cells are obtained from peripheral blood, placement of vascular access in children usually requires sedation or general anesthesia. There is little evidence to support the avoidance of nitrous oxide for harvesting procedures, a concern raised in the past because nitrous oxide affects methionine synthase activity and DNA synthesis.²⁶⁴

In view of the wide range of possible complications, the many issues enumerated earlier for children with cancer must be considered for children undergoing HSCT (see Table 9-18). Radiation, glucocorticoids, mucositis, and chronic GVHD may contribute to an airway that is friable and a neck that is scarred, thereby increasing the risks of airway trauma, dental injury, and difficult tracheal intubation. Chemotherapy and GVHD may affect the skin and make venous access difficult. Chronic GVHD can lead to sclerodermatous changes, which can profoundly restrict range of motion, and sicca syndrome, which may necessitate use of artificial tears. GVHD may alter gut motility and delay gastric emptying. Immune compromise increases the risk of infection from vascular access lines and therefore mandates meticulous technique at all times. Chemotherapy may compromise cardiac and pulmonary function, alter hepatic metabolism of medications, and limit renal excretion of medications and fluids. Immune compromise and modifications resulting from transplantation require special processing of blood components, as recommended by hematology and blood bank consultants (see Tables 9-3, 9-4, and 9-5). Only irradiated, leukocyte-reduced, cytomegalovirus-negative (when the recipient is cytomegalovirus negative) blood components should be administered, and blood typing depends on engraftment of donor antigens. It is critical to coordinate the choice of blood products with the transplant service because often the blood type changes from that of recipient to that of donor.

In summary, hematologic disorders in childhood pose a wide array of challenges for the anesthesiologist caring for children. The considerations described in this chapter also provide many opportunities for collaboration with hematology-oncologists and surgeons to optimize perioperative outcomes for children with these disorders.

Annotated References

Guzzetta NA, Miller BE. Principles of hemostasis in children: models and maturation. Paediatr Anaesth. 2011;21:3–9.

This review article summarizes the fundamentals of hemostasis and highlights the differences in thrombosis and coagulopathy from the preterm neonate through childhood. The impact of disease states on hemostasis are also discussed.

Key NS, Derebail VK. Sickle-cell trait: novel clinical significance. Hematology. 2010;2010:418–422.

This review discusses sickle cell trait as a risk factor for adverse outcomes, focusing on its impact on exercise, renal function, and venous thromboembolism.

Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient—part 1: a review of antitumor therapy. Paediatr Anaesth. 2010;20:295–304.

This article briefly reviews the current principles of cancer therapy and the general mechanisms of toxicity to the child, focusing on the impact to perioperative care and decision making.

Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient—part 2: systems-based approach to anesthesia. Paediatr Anaesth. 2010;20:396–420.

A systems-based approach is used to assess the impact of the tumor and its treatment on children, and relevant anesthetic considerations are discussed.

Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient—part 3: pain, cognitive dysfunction, and preoperative evaluation. Paediatr Anaesth. 2010;20:479–489.

This paper discusses the psychosocial impact of cancer and pain syndromes that should be considered in the perioperative period. A discussion of preanesthetic testing and evaluation in children with cancer follows.