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

Prevention of Alloimmunization

Congenital hemolytic anemias (including sickle cell disease and thalassemia)

Hypoproliferative anemias likely to need multiple transfusions

Aplastic anemia

Myelodysplasia/myeloproliferative syndrome

Plasma cell dyscrasias

Hematopoietic stem cell transplants

Hematopoietic malignancies

Therapy for Preexisting Conditions

Recurrent, severe febrile hemolytic transfusion reactions

Known HLA alloimmunization

Possible Uses

Alternative to cytomegalovirus-seronegative components (see Table 9-5)

Human immunodeficiency virus–infected patients

TABLE 9-4 Indications for Irradiation of Cellular Blood Components

Well-Defined Indications

Hematopoietic stem cell transplantation

Actual or anticipated congenital cell-mediated immunodeficiency

Intrauterine transfusion or after intrauterine transfusion

Directed donation from blood relative or HLA-matched donor

Hodgkin disease

Acute lymphocytic leukemia

Immunocompromised organ transplant recipient

Probable Indications

Malignancy and organ transplantation treated with immunosuppressive therapy

Exchange transfusion in neonate

Extracorporeal membrane oxygenation in neonate

Low–birth-weight neonate (<1200 g)

Human immunodeficiency virus–infected patient with opportunistic infection

Possible Indications

Term neonate (<4 months)

Human immunodeficiency virus–infected patient

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

Well-Defined Indications

Low–birth-weight neonate (<1200 g)

Human immunodeficiency virus–infected patient

Recipient of seronegative allogeneic organ or hematopoietic stem cell transplant or prospective recipient

Pregnant woman

Intrauterine transfusion

Possible Indications

Hodgkin disease or non-Hodgkin lymphoma

Recipient of immunosuppressive therapy

Candidate for autologous hematopoietic stem cell transplantation

Hereditary or acquired cellular immunodeficiency

Probable Absence of Indications

Seronegative term infant

Seropositive pregnant woman

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.

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

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