Emergency Management of Children with Sickle Cell Anemia
Authors: Kevin J. McSherry, MD, Assistant Professor of Pediatrics, Department of Emergency Medicine, The Mount Sinai Medical Center, New York; Bonny J. Baron, MD, Associate Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center, Kings County Hospital Center, Brooklyn, NY; Karen L. Stavile, MD, Assistant Professor, State University of New York, Downstate Medical Center; Associate Director of Emergency Services, Kings County Hospital Center, Brooklyn, NY
Peer Reviewer: J. Stephan Stapczynski, MD, Chair, Emergency Medicine Department, Maricopa Medical Center, Phoenix, AZ
Patients with sickle cell disease (SCD) frequently present to the emergency department. Life-threatening infections and cerebrovascular accidents remain a constant threat throughout the lifetime of individuals with SCD. Vaso-occlusion can produce devastating effects in virtually every major organ system. Acute or chronic multi-system organ failure, long-term disabilities, and early death may occur. Emergency physicians must be familiar with the major clinical manifestations, potential complications, and management of patients with SCD.
— The Editor
Introduction
SCD consists of a group of inherited red blood cell (RBC) disorders characterized by chronic hemolytic anemia and intermittent episodes of vaso-occlusive phenomena. Sickle cell anemia arises from a single DNA mutation in the amino acid sequence of the beta-globin chain at the 6th codon, with replacement of glutamic acid for valine. This hemoglobin variant is designated hemoglobin S (HbS). A closely related mutation at the same DNA site, results in formation of hemoglobin C (HbC). The sickle hemoglobin gene is frequently co-inherited with other beta- and alpha-chain abnormalities that can alter the clinical expression of the disease. Co-inheritance of the genes for both HbS and HbC produces HbSC disease, the second most common variant of SCD. Patients with HbSC generally have milder illness. Similarly, beta-thalassemia may be co-inherited with the allele for HbS, giving rise to a spectrum of disease from HbS-beta+ thalassemia (a gene that reduces normal beta-globin protein synthesis) to HbS-beta0 thalassemia (a gene that causes complete absence of normal beta-globin protein synthesis). The degree of anemia and severity of illness correlates with the output of the thalassemic gene (i.e., patients with HbS-beta0 thalassemia tend to have more severe complications than those with HbS- beta+ thalassemia). Patients with co-existing alpha thalassemia tend to have less severe anemia as a result of lower red cell hemoglobin concentrations. The effect on the clinical manifestations of disease is variable.
Approximately one of every 10 African American adults carries the gene for HbS. Because the gene for HbS is inherited in an autosomal recessive fashion, one of every 400 African American children will have SCD. In addition to African Americans, SCD also is found in people of Caribbean, Central and South American, Mediterranean, Indian, and Middle Eastern descent. Inclusion of all of the sickle cell variants increases the relative incidence of SCD to approximately one in 300 children.1
Individuals who inherit a single gene for HbS (or HbC) carry the trait but typically are unaffected with the disease. They may, of course, transmit the genetic abnormality to their offspring.
Clinically significant hemoglobin variants can be readily identified by newborn screening. Universal screening is performed routinely in 44 states, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands. Given the recent influx of immigrants to the United States—particularly those from Western African nations—it is critical to consider SCD in children who have not been tested for the condition when they present to the ED with one of the clinical conditions associated with SCD.
This article reviews the associated clinical conditions, current management, and recent advances in the treatment of patients with SCD.
Pathophysiology
Polymerization of deoxy HbS is an essential component in the development of vaso-occlusion. The HbS molecule is poorly soluble when deoxygenated. The polymer that forms generally takes the shape of rope-like structures that distort the red cell membrane leading to formation of the classic crescent or sickle shape (dense cells), membrane rigidity, and a marked decrease in red cell deformability. This rigidity impairs the cells’ ability to traverse the microcirculation in various organs in the body. Polymerization of sickle hemoglobin can occur under any of the following conditions: dehydration, acidosis, hypertonic milieu, elevated body temperature, and low blood flow states. Red cell trapping of the deformed erythrocyte in the microcirculation leads to tissue ischemia. If not corrected, tissue infarction and organ damage will occur. Rapid, reversible episodes of polymerization ultimately lead to red cells with permanently damaged membrane structure and function, altered cell volume, and increased adherence to vascular endothelium. Repeated cycles of deformation eventually result in irreversibly sickled cells, which can be identified on routine blood smear.
The rate of polymerization of deoxy HbS is directly related to the HbS concentration within red cells and is affected by the presence of other non-S hemoglobins.2 HbS solubility also is affected directly by such factors as fractional oxygenation, pH, temperature, ionic strength, and organic phosphates.3
A decrease in blood pH below 7.4 in tissue capillaries results in twice the normal decrease in oxygen affinity, leading to a large release of oxygen from red cells and increased risk of sickling.4 Polymerization of HbS is enhanced at higher body temperatures.5 2,3 Diphosphoglycerate (2,3-DPG) is the primary modulator of oxygen affinity in the red cell. An increased level of 2,3-DPG favors polymerization by lowering oxygen affinity, reducing intracellular pH (both of which increase deoxy HbS), and by directly affecting the conformation of deoxy HbS.6 Younger red cells and reticulocytes tend to have higher concentrations of 2,3-DPG.
Fetal hemoglobin (HbF) and hemoglobin A2 (HbA2) inhibit polymerization because they cannot be incorporated into the sickle polymer.7 Variable amounts of these non-S hemoglobins are found in individuals with SCD and can modulate the severity of clinical disease.
The predominant hemoglobin in all newborn infants is fetal (HbF), a tetramer composed of two alpha and two gamma globin chains and designated as alpha2, gamma2. There is a gradual changeover to normal adult hemoglobin (alpha2,beta2) between the last trimester of pregnancy and the first year of life. Individuals who are homozygous for HbS (or doubly heterozygous for HbS and other non-S hemoglobins) will begin to accumulate sickle hemoglobin within their red cells sometime during early infancy. Thus, clinical manifestations of SCD are infrequently seen before 6 months of age, except under conditions where red cell production in the infant has been accelerated (e.g., an infant with SCD and an exaggerated physiologic anemia).
Laboratory Findings in Sickle Cell Disease
Chronic hemolysis with relative compensatory reticulocytosis is characteristic of SCD. Average hemoglobin and hematocrit levels in one reported series of patients was 7.9 g/dL and 22.9 %, respectively, with an absolute reticulocyte count (red cell count x percentage of reticulocytes) of 501,000/uL (normal: 50 80,000/ uL).8 Elevated levels of unconjugated bilirubin and serum lactate dehydrogenase (LDH) and a low serum haptoglobin — which binds free hemoglobin levels released during hemolysis — are also characteristic of SCD. Mean serum bilirubin levels are higher in patients with SCD than in those with HbSC or HbS-beta thalassemia due to the higher rate of hemolysis. If the MCV is not elevated, one should consider the possibility of sickle beta-thalassemia, co-inherited alpha thalassemia, or iron deficiency anemia (IDA). IDA is found in as many as 20% of children with SCD.9 The blood smear in a typical patient with SCD will reveal sickled red cells, moderate anisocytosis, polychromasia (due to reticulocytosis), target cells, and occasional Howell-Jolly bodies (indicative of splenic hypofunction).
Folate and/or iron deficiency may result from increased utilization of folate and urinary iron loss.10,11
Data from the Cooperative Study of Sickle Cell Disease (CS-SCD) found that in patients with SCD, mean white blood cell (WBC) counts and platelet counts were higher than normal. WBC and platelet counts were not elevated in patients with HbSC disease or sickle beta-thalassemia.8
HbF and A2 levels often are slightly to moderately elevated. In certain subpopulations of patients with SCD (e.g., Arab-Indian and Senegalese haplotypes), HbF levels above 20% may be found. Many of these patients will have a milder clinical form of the disease.12,13
A recent study of 392 infants diagnosed with SCD or HbS-beta0thalassemia attempted to identify factors predictive of adverse outcomes in later life.14 An adverse outcome, defined as stroke, frequent painful episodes or recurrent chest syndrome, occurred in 18% of children in this study. Three significant predictors of adverse outcomes were identified:
- Dactylitis before age 1 year (relative risk [RR] 2.6)
- Hemoglobin concentration less than 7 g/dL (RR 2.5)
- Leukocytosis in the absence of infection (RR 1.8).14
The Anemia of Sickle Cell Disease
The anemia of SCD is typically a chronic, compensated hemolytic anemia with an appropriate reticulocytosis. The average life span of red cells of affected individuals is 7-20 days (normal 100-120 days).15 Clinically, this manifests as varying degrees of anemia with a brisk compensatory reticulocytosis, tachycardia, a hyperdynamic flow murmur, scleral icterus, mild jaundice, hyperbilirubinemia, and elevated LDH levels. Characteristic findings on blood smear include sickle shapes, target cells, polychromasia, anisopoikilocytosis, and thrombocytosis.
There are two conditions in which an acute decline in hemoglobin concentration can develop in patients with SCD: splenic sequestration crisis and aplastic crisis. These are true hematologic emergencies associated with appreciable morbidity and mortality. (See Figure 1.)
Splenic Sequestration Crisis
Acute splenic sequestration is a life-threatening emergency that can occur without warning in children with SCD. Vaso-occlusion within the spleen and splenic pooling of red cells and plasma can result in an abrupt decline in hemoglobin concentrations and blood volume.16 The spleen may enlarge dramatically within several hours. This condition typically affects infants and young children with SCD whose spleens have not yet undergone autoinfarction and fibrosis. Splenic sequestration may be the initial symptom in as many as 20% of children with SCD and one-third of children will have acute splenic sequestration crisis before 2 years of age.17 Children with HbSC and HbS-beta thalassemia are at continued risk for splenic sequestration throughout childhood because of the lower incidence of splenic scarring and atrophy associated with these SCD hemoglobin variants.18
There is a 10-15% mortality rate from splenic sequestration if not recognized rapidly and managed effectively and a 50% recurrence rate in survivors. Therefore, splenectomy is recommended after the first episode of splenic sequestration.19
Clinically, patients with splenic sequestration present with pallor, marked tachycardia, splenomegaly, abdominal distention, irritability, and hypovolemic shock. Laboratory findings include profound anemia with a brisk reticulocytosis. Occasionally, mild thrombocytopenia, secondary to sequestration of platelets, is seen.
Treatment is directed primarily toward restoration of circulating blood volume to maintain adequate tissue perfusion. Emergent transfusion of packed RBCs is indicated for severe anemia (Hb < 4-5 g/dL) or cardiovascular compromise. Cefotaxime or cefuroxime should be given to febrile patients for presumptive treatment of bacterial sepsis.
Patients with sequestration crisis should be hospitalized in a monitored setting. Serial blood counts are followed to determine the need for additional red cell transfusions. As splenic sequestration abates, previously sequestered red cells return to the circulation. Blood volume and hemoglobin level may rise above posttransfusion levels.
Aplastic Crisis
Transient aplastic crisis (TAC) results from the transient arrest of red cell production in patients with hemolytic anemia. As a consequence of rapid hemolysis and shortened red cell survival in patients with SCD, a dramatic decline in hemoglobin occurs over a short period of time, often within several days.
Parvovirus B19 is the infective agent most often associated with TAC. Parvovirus B19 is the causative agent of erythema infectiousum ("fifth" disease), a benign, self-limited illness associated with a characteristic facial rash.20 Parvovirus B19 may affect proliferating red cell progenitors in the bone marrow with marrow suppression typically lasting from 2 to14 days. More than 60% of children with SCD have serologic evidence of parvovirus B19 infection by the age of 15 years. Recurrent infection with parvovirus is rare.21 TAC also has been associated with Streptococcus pneumoniae, Salmonella, and Epstein-Barr virus infections.
Clinically, patients with TAC present with pallor, fatigue, and tachycardia. In contrast to acute sequestration crisis, spleno-megaly is absent. Laboratory findings include marked anemia and severe reticulocytopenia. Red cell transfusions are indicated to ameliorate symptoms of severe anemia while waiting for the eventual recovery of native red cell production.
When severe anemia has developed over several days, patients may be at risk for volume overload if the volume is corrected too quickly. Therefore, correction of anemia with slow packed red cell transfusion, at 4-5 mL/kg over 4 hrs, is recommended, and administration of furosemide should be considered. Serial CBC and reticulocyte counts should be monitored. Recovery from TAC initially is heralded by the appearance of reticulocytes in the blood smear and ultimately by return to baseline levels of anemia.
Major Clinical Complications of SCD
Acute Painful Episodes (APE). The most frequent complication in children with SCD is an acute painful episode, formerly referred to as a painful vaso-occlusive crisis. Fever, infection, dehydration, exposure to cold, stress, menses, alcohol consumption, and nocturnal hypoxemia are typical precipitating factors leading to APE. Acute painful episodes account for nearly 90% of all SCD patient visits to the ED and nearly 70% of SCD hospital admissions.22
There is much variability in the frequency and severity of APE experienced by patients with SCD. In a large study by Powars, one third of patients rarely suffered painful episodes, another third had between two and six episodes per year requiring hospitalization; the most severely affected group had more than six episodes per year.22 Similar results were found in a prospective study of 3578 patients by the Cooperative Study of Sickle Cell Disease (CS-SCD).23
The most common anatomical sites for APE are the vertebrae, ribs, and long bones of the extremities. Pain generally is diffuse and may be accompanied by low-grade fever and mild swelling of affected areas. Children often experience pain in the same sites with repeated episodes, although this is not always the case. Although far less common than APE, osteomyelitis must be included in the differential diagnosis. Nonaccidental injury and trauma are additional considerations.
Dactylitis (hand-foot syndrome) is painful swelling of the hands or feet and often the first sign of disease in young infants with SCD. It is seen rarely in children older than 4 years. Dactylitis is believed to arise from infarction of the metacarpal or metatarsal bones. Typically, the infant will refuse to grasp an object placed in the affected hand or to bear weight on his/her feet. Erythema and low-grade fever may be present. Other than soft-tissue swelling, there is no radiologic evidence that can identify an acute episode of dactylitis. Recurrent dactylitis can lead to a mottled appearance of bones on x-ray and possibly to shortening of the affected metacarpal, metatarsal, or phalangeal bones. Treatment of dactylitis consists of hydration and administration of analgesic agents, anti-inflammatory medications, and hot packs. Febrile patients should receive antibiotics after blood cultures are obtained.
Chest or back pain is a particularly worrisome symptom in patients with SCD. Painful rib infarctions can lead to splinting, atelectasis, and hypoventilation, which can generate a worsening cycle of infarction, hypoxemia, and progressive sickling. Clinical presentation, in addition to pain, may include tachypnea, labored breathing, diminished or absent breath sounds and hypoxia. Continuous pulse oximetry should be instituted; maintain oxygen saturation levels of 92% or greater. A chest x-ray is indicated in any patient with hypoxia, respiratory distress, abnormal or diminished breath sounds, fever, cough, or worsening symptoms. Although adequate pain control should be provided, dosing of opioid analgesia must be monitored carefully to avoid hypoventilation. The differential diagnosis of chest or back pain includes acute chest syndrome, pulmonary infarction, and pneumonia (discussed later in text).
Abdominal pain is especially problematic in patients with SCD. Pain is believed to arise from ischemia of the mesenteric circulation. Tissue ischemia and hypoxia can lead to progressive sickling and infarction of various organs and tissues, particularly the liver and spleen.
Hepatic infarction typically presents with right upper quadrant (RUQ) tenderness, jaundice, scleral icterus, nausea, and vomiting. Liver dysfunction and hepatomegaly can occur as a result of intrahepatic sickling, transfusion-acquired infection, hemosiderosis, and autoimmune hepatitis. Analgesia and hydration are the mainstays of treatment. Asymptomatic, pigmented gallstones have been identified in children as young as 3 years and occur in about 70% of patients with SCD.22
Acute splenic enlargement with sequestration crisis can present with abdominal pain. In most cases, splenic infarction occurs silently over time. Gradually, the child develops splenic hypofunction that ultimately leads to a functional asplenic state.
The clinician must remember that in addition to abdominal complications specific to SCD, the differential diagnosis of abdominal pain includes more commonly occurring disorders (e.g., acute appendicitis, gastroenteritis, constipation). Radiographic evaluation should be considered in patients who have an atypical presentation of an acute painful episode.
There are few clinically useful laboratory tests that can distinguish APE from other causes of abdominal pain. The level of several acute phase reactants (e.g., C-reactive protein, fibrinogen, LDH, interleukin-1, tumor necrosis factor, and serum viscosity) change during acute painful episodes, but the clinical relevance of these tests is not clear. Laboratory studies of the density distribution of sickle cell subpopulations and the rheologic properties of blood are promising but have little practical value in the clinical assessment of painful crises.
Management of Acute Painful Episodes. The initial management of a child with APE includes oxygen administration to maintain arterial oxygen saturation levels above 92% and intravenous hydration provided when necessary to avoid the development of dehydration and potential worsening of the painful crisis.
The use of pain medications for the management of painful crises in patients with SCD is complex. Wide variation in treatment regimens exists among practicing physicians, and the subjective interpretation of pain is influenced by the patient’s clinical condition, psychological state, and prior experience with pain control. Patients and their families typically begin medical intervention at home prior to the patient’s visit to the ED, according to their primary physician’s instructions. Treatment generally includes oral hydration and administration of analgesic agents, heat packs, and rest. Visual pain scales can be employed in the ED, even in the nonverbal child, to help quantify the level of discomfort. Most chronic patients are familiar with previous effective pain strategies and can help direct the physician to provide adequate pain control.
An accepted approach to pain management in the acute setting is to titrate dosage of analgesia until adequate pain control is achieved. The goal is to diminish the patient’s pain symptoms as quickly as possible. Repeated doses of analgesic agents are administered at frequent intervals until the patient experiences adequate pain relief. This approach requires careful and continuous monitoring, particularly in patients who are at risk for the development of acute chest syndrome. Patients who fail to attain satisfactory pain relief after four to six hours of ED treatment warrant hospitalization.
Physicians are sometimes reluctant to administer opioid analgesic agents at doses that may be required to alleviate painful symptoms. Fear of complications from overdosing patients with opioids along with failure to recognize the severity of patients’ pain, may contribute to physicians underdosing of analgesic agents. Unfortunately, there are no clinically useful laboratory indicators to accurately gauge the patient’s level of pain.
Acetaminophen with codeine or ibuprofen should be given for mild to moderate pain. Some patients may have taken these medications prior to their arrival in the ED. These patients should receive more potent analgesic agents. Ketorolac also can be given; it is approved for use in children older than 16 years or weighing more than 50 kg. Ibuprofen and ketorolac should not be used in combination because of their additive side effects. Contraindications to ketorolac and ibuprofen include gastritis, peptic ulcer disease, coagulopathy, and renal impairment.
Morphine sulfate (MS) is among the most frequently prescribed opioid analgesic agents for patients with SCD. The recommended starting dose is 0.1 0.15 mg/kg/dose, although many patients require higher doses to achieve pain relief. Additional doses of 0.05 mg/kg/dose can be given at intervals of 15-30 minutes, as needed, to achieve adequate pain control. Meperidine and hydromorphone can be substituted in patients who report adverse reactions to MS. Repeated doses of meperidine should be avoided because of the reported risk of seizures.
Patient controlled analgesia (PCA), using devices designed to administer opioids on demand, has been effective in allowing patients to participate in the management of their symptoms. Children as young as 6 years can be instructed in the use of this method of opioid administration. Total MS dose via PCA is 0.05 0.1 mg/kg/hr with one-third to one-half total maximum dose as a continuous infusion and between one-half and two-thirds via PCA boluses. Meperidine also is available for PCA, but its use should be restricted due to potential complications, as previously described.
Many physicians, health care workers, and parents express concern regarding the addictive potential of narcotic analgesic agents. Occasionally, an adolescent or young adult patient develops tolerance to narcotic analgesia and requires increased doses of medication to achieve pain relief. Some patients with SCD may have chronic pain associated with their illness (e.g., avascular necrosis of the femoral head) and require low-dose opioid analgesic agents on a regular basis.
Physicians are sometimes faced with patients who appear to be in severe pain despite seemingly adequate doses of analgesia. Patients who repeatedly present to the ED and require unusually large doses of analgesia, often without pain relief, should be considered to have some degree of opioid tolerance or addiction. Such patients require hospitalization and consultation with a pain management service for therapeutic intervention.
In general, children and adolescents with SCD do not have tolerance or addiction to opioids. The perception by some ED physicians that their patients are exhibiting drug-seeking behavior should not preclude the appropriate administration of analgesia in the acute setting with appropriate discussions with their primary physician.
Acute Chest Syndrome. Acute chest syndrome (ACS) is a serious and rapidly progressive condition that is the leading cause of death from SCD.24 The low pressure, slow flow rate in the relatively hypoxic environment of the pulmonary circuit is an ideal environment for the polymerization of sickle hemoglobin. Bacterial pneumonia, pulmonary infarction with thrombosis, and embolic phenomena from fat embolism and bone marrow infarction are the principal causes of ACS. Infection is common in children younger than 5 years with ACS. Bacteremia is found in 3.5% of cases, with a higher incidence in infants.24 While Streptococcus pneumoniae and Haemophilus influenzae are the most common organisms, Mycoplasma pneumoniae and Chlamydia are being seen with increased frequency in children.25 Thromboemobolic phenomenon and fat and bone marrow embolism leading to microvascular pulmonary infarction have been well described in a number of adult autopsy studies,26,27 however, there is little data in children.
Typically, patients with ACS present with back, chest, or rib pain, tachypnea, difficulty breathing, and cough. Fever and hypoxia may be present. Lung sounds may be deceptively clear, but the patient is often in extreme distress. A chest radiograph is essential and may show evidence of infarction including uni- or multilobar infiltrates, an elevated hemidiaphragm, and pleural effusions. Laboratory findings typically include leukocytosis, a declining hemoglobin concentration, thrombocytosis or thrombocytopenia, and elevations in LDH and bilirubin levels.
Oxygen should be provided to maintain arterial oxygen saturation levels above 92%. Adequate analgesia without over sedation should be given. Aggressive hydration should be avoided because of the risk of pulmonary edema. Incentive spirometry (10 breaths q 2 hr while awake) is a useful adjunct for the prevention of pulmonary complications.28 Bronchodilator therapy also may play a role in management because many patients with SCD may have concurrent hyperreactive airway disease. Worsening hypoxemia and progressive pulmonary infiltrates, despite therapy, signal impending respiratory failure and possible multi-organ failure.29
Intravenous antibiotic agents are indicated in the presence of pneumonic infiltrates because it is not possible to distinguish infection from infarction. Antibiotic agents should treat both community-acquired and atypical pulmonary pathogens. Cefotaxime or cefuroxime plus azithromycin or erythromycin are recommended. Prophylactic penicillin therapy can be discontinued while the patient is receiving intravenous antibiotic therapy.
Opioid analgesia should be administered judiciously to patients with ACS to avoid potential respiratory depression, the development of pulmonary edema, and further hypoxemia. Ibuprofen and ketorolac are useful adjuncts for mild to moderate symptoms. Opioid analgesic agents (e.g., morphine sulfate, meperidine, or hydromorphone) should be provided to control moderate to severe pain.
Type and cross-match for packed RBCs should be obtained at the time of initial blood drawing. Blood should be sickle negative and matched for RBC minor-antigen phenotypes to reduce red cell antibody formation. Simple transfusion of leukocyte-depleted packed RBCs improves oxygenation and should be considered early in the course of treatment of ACS. Exchange transfusion is indicated in refractory cases or in the presence of progressive pulmonary infiltrates.30 Unstable patients with acute chest syndrome can deteriorate rapidly and should be monitored closely in an intensive care setting.
Inhaled nitric oxide is currently under investigation as a potential therapy for ACS. It is believed to down-regulate the expression of vascular cell adhesion molecule-1 (VCAM-1), which may play a role in red cell adhesion to endothelium exposed to hypoxic conditions. While anecdotal reports exist, there is currently insufficient evidence to support the use of nitric oxide in the treatment of ACS.
Patients who have experienced ACS are at risk for recurrent episodes. To reduce the risk of recurrent ACS in these patients, some treatment centers are recommending prophylactic RBC transfusions monthly with a goal of maintaining HbS levels at or below 40%.
Hydroxyurea (HU), an alkylating agent that is relatively nontoxic, well tolerated, and has not been shown to induce tumor formation, has been shown to reduce the incidence of recurrent ACS in adults.31 Several studies in children have shown the efficacy of this drug for reducing the severity of clinical symptoms.32-35 Myelosupression from the drug is dose dependent and reversible. Compliance remains an important issue with the long-term administration of this medication.
Trials of recombinant human erythropoietin (rhEpo) either alone or in combination with HU have shown conflicting results; rhEpo currently is recommended for patients at risk for ACS who are unresponsive to HU therapy alone.36
Long-term sequelae of patients with ACS include restrictive and obstructive lung disease, pulmonary hypertension, and chronic hypoxemia. Airway hyperreactivity that is not associated with asthma and obstructive sleep apnea have been described in children with SCD and a history of ACS.37,38
Central Nervous System Infarction/Hemorrhage. A cerebrovascular accident (CVA) is a devastating complication in children and adults with SCD. The reported age-adjusted incidence is 0.61-0.76 per 100 patient-years during the first 20 years of life, with significantly lower values in patients with HbSC, HbS-beta+ thalassemia and HbS-beta0 thalassemia (0.15, 0.09, and 0.08, respectively). The likelihood of having a first CVA by 20 years of age was 11% for patients with HbSS compared with 2% for patients with HbSC.39
Stroke usually is associated with vascular occlusion in the large cerebral arteries; an ischemic event is more common in children between the ages of 2 and 9 years. Hemorrhagic stroke occurs more frequently in young adults between the ages of 20 and 29 years.40 Recurrent strokes occur in approximately two-thirds of patients within two years of the initial episode; the risk is higher in younger children.
Using multivariate analysis, the CS-SCD has identified several major risk factors for cerebral infarction. These risk factors include prior TIA, low steady-state hemoglobin concentration, an episode of ACS occurring in the preceding two weeks, and elevated systolic blood pressure. Patients with stroke characteristically present with hemiparesis, dysphasia, gait disturbance, and/or altered level of consciousness. Physical examination reveals the presence of an apparent neurologic deficit.
Transcranial Doppler (TCD) is a noninvasive clinical study that has become an important tool to assess the risk for stroke. TCD measures the velocity of blood flow in the large intracranial vessels; velocities greater than 200 cm/sec in the middle cerebral or internal carotid artery are highly associated with an increased risk of stroke.41 TCD is used routinely as a screening tool in many pediatric sickle cell centers. Recommended interventions for children identified at high risk for stroke include initiation of a prophylactic transfusion program, administration of hydroxyurea therapy, and consideration for bone marrow transplantation.
Intracranial hemorrhage (ICH) accounts for approximately one-third of strokes in patients with SCD.39 Bleeding may occur in the subarachnoid, intraparenchymal, or intraventricular regions. The CS-SCD has identified two major risk factors for hemorrhagic stroke: low steady-state hemoglobin concentrations and increased steady-state leukocyte count. The mortality rate in patients with ICH is 24-50%.39
The most common presenting clinical symptoms include headache, vomiting, neck stiffness, and altered level of consciousness. Patients with an intraventricular hemorrhage or large intraparenchymal hemorrhage with extension into the ventricular system may deteriorate during the first 48 hours because of obstructive hydrocephalus and ventricular dilatation. Emergent ventricular drainage may be necessary. Immediate neurosurgical consultation should be obtained for any patient presenting with ICH.
A CVA is a true hematologic emergency and requires rapid and aggressive intervention (Figure 2). Immediate evaluation of the patient’s airway, breathing, and circulation should be followed by rapid assessment of neurologic disability. Vascular access should be established with large bore intravenous catheters. Blood should be obtained for complete blood count, reticulocyte count, electrolyte levels, liver functions, coagulation profile, and type and cross-match, anticipating that a double volume exchange transfusion (estimate 70mL total blood volume per kg) will take place. The blood bank should be notified of the immediate requirement for several units of blood to be reconstituted alternately with normal saline or albumin to a final hematocrit level approximating 30%. A double volume exchange transfusion is recommended after the patient is stabilized. Transfusion will not reverse existing neurologic damage but may prevent progressive neurologic deterioration. Anticonvulsants are indicated when seizures are present. Admission to an intensive care unit is warranted.
Appropriate radiologic studies should be obtained. Initial CT findings may not reveal an infarction; abnormalities may not appear for up to six hours post-infarction. An MRI / MRA may be needed to delineate the extent of neurologic injury. Angiography is indicated for patients with ICH to identify surgically treatable causes of bleeding (e.g., aneurysms).
Despite the inherent ability of young children to recover neurologic function following CVA, there remains significant morbidity and mortality associated with this condition.
Bacterial Sepsis. Acute bacterial sepsis is the leading cause of death in children with SCD younger than 5 years.43 Patients typically present with fever and leukocytosis that may progress to DIC, multi-organ failure, and septic shock. The onset of bacterial sepsis may be rapid, and deterioration can lead to death within several hours.
During the first two years of life, repeated, silent infarctions of the spleen may occur, leading to autoinfarction, functional asplenia, and inability to opsonize and clear encapsulated organisms from the circulation. The two most common organisms associated with overwhelming bacterial sepsis in the sickle cell population are Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (HiB). The risk of pneumococcal sepsis in children with SCD is estimated at 400 times greater than in the general population. The risk for HiB sepsis in SCD is about four times greater.42-43 Children with sickle cell variants are at less risk for bacterial sepsis because they generally maintain some splenic function throughout their lives.
The advent of pneumococcal and HiB vaccines given during the primary immunization series has resulted in a dramatic decline in the incidence of pneumococcal disease and invasive HiB infection in the pediatric population;44 nevertheless, vaccination is not entirely protective in all cases, some children may not have completed their scheduled vaccinations, and strains exist that are not covered by the vaccine.45
The risk of recurrent pneumococcal sepsis is increased in patients who have had a prior episode of sepsis. Bacteremia may be associated with acute chest syndrome and is more likely to occur in infants.24
Any child who presents with fever (i.e., temperature greater that 38° C) should be evaluated immediately for signs of infection and shock. Antibiotic therapy with broad-spectrum coverage against pneumococcus and HiB should be administered. Cefuroxime or cefotaxime is recommended. Clindamycin can be used in patients with suspected cephalosporin allergy. Vancomycin should be considered in patients with evidence of severe infection. A chest x-ray and blood and urine cultures should be obtained. The administration of systemic antibiotics should not be delayed pending acquisition of cultures.
Bacterial pneumonia may be caused by Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella, S. pneumoniae, and HiB in patients with SCD. Respiratory viruses are also a common cause of pneumonia. The typical clinical presentation includes fever, cough, dyspnea, tachypnea, hypoxemia, and leukocytosis. These patients are at risk for development of acute chest syndrome. Meningitis in SCD occurs most commonly in infants and young children. It usually is caused by S. pneumoniae and HiB.
Bone and Joint Complications
Acute painful episodes characteristically involve the vertebrae, ribs, and long bones of the extremities. Refer to the previous discussion in the section entitled Acute Painful Episodes.
Osteomyelitis. Osteomyelitis is an infection of the cortical bone. It occurs more readily in children with SCD than in the general population. Salmonella species, distinctly uncommon in healthy children, is the most common infecting organism, followed by Escherichia coli and other gram-negative bacteria. Staphylococcus accounts for only about one-quarter of all cases of osteomyelitis in SCD.46,47
Children typically present with fever, pain, tenderness, and localized swelling of the hand, foot, over a joint, or on the shaft of an extremity. There may be overlying cellulitis. The differential diagnosis of osteomyelitis includes acute painful episode and septic arthritis. Limitation of movement is generally more pronounced with septic arthritis. Unremitting pain, despite adequate analgesia, should heighten one’s suspicion for osteomyelitis.
Orthopedic consultation should be sought to obtain a bone aspirate or biopsy for culture. Care must be taken to avoid introducing infection into the bone from overlying cellulitis. Initial radiographs may be negative because several days to a week may be required to develop radiologic evidence of infection. Blood cultures and an erythrocyte sedimentation rate (ESR) measurement should be obtained. The ESR, typically very low (< 5 mm) in children with SCD, will be markedly elevated in children with osteomyelitis. Radionuclide bone imaging may be useful to localize the site of involvement. An important caveat: Patients with SCD frequently have abnormal bone scan findings due to previous bone infarctions. Areas of increased radionuclide up-take, which reflect healing bone, can make interpretation difficult.
Antibiotic therapy should be directed against both Salmonella and Staphylococcus species. Nafcillin or oxacillin plus ceftazidime are recommended. Vancomycin or clindamycin plus ceftazidime can be substituted in penicillin allergic patients. Treatment may take as long as 6 weeks for complete resolution of the bone infection. Pain management should be directed by the patient’s level of discomfort.
Avascular Necrosis of Femoral or Humeral Head. Avascular necrosis (AVN) of the femoral or humeral head is a well-known complication of SCD. AVN can appear in children as young as 5 years.46 It occurs more frequently in children and young adults with HbSC disease, perhaps because of their higher level of physical activity. The natural history of AVN is progressive degeneration of the bony capsule of the femoral head, which leads to decreased mobility, pain, limp, and leg-length discrepancies. Radiologic evidence of flattening of the femoral head may be seen in as many as half of the SCD patients who are clinically asymptomatic. AVN can also occur in the proximal humeral shaft, but because this bone is nonweight bearing, it is generally of less clinical consequence.
Conservative treatment with nonweight bearing ambulation, bed rest, analgesic agents, adequate hydration, and blood transfusions are advocated. However, the general course of the disease is one of progressive deterioration and loss of function.
Priapism
Priapism is a painful, sustained erection of the penis in the absence of sexual stimulation. This abnormal erection can last from several hours up to a few days. The pathophysiology involves venous vaso-occlusion with subsequent engorgement of the penis (low-flow priapism). The persistent erection is maintained because of decreased penile venous outflow. Engorgement usually involves the corpora cavernosum, but spares the glans and corpora spongiosum. In postpubertal males, engorgement may affect the glans and corpora spongiosum.49 Clinically, the patient presents with a painful erection, which can be acute, chronic, or acute on chronic. An estimated 642% of males with SCD are affected. There are two peak incidences: ages 5 to 13 years and 21 to 29 years.49
Sickle cell priapism is a true urologic emergency. Prolonged ischemia may result in irreversible corporeal fibrosis and destruction of erectile tissue, which may lead to permanent erectile dysfunction.50
Early intervention allows the best chance of functional recovery. Initial therapy should include intravenous hydration and analgesic agents. Simple or exchange transfusions can be given in refractory cases. Urologic consultation should occur at the time of patient presentation and needle aspiration and irrigation may be necessary for patients who are refractory to medical management. Repeated aspirations can be done until detumescence for more than one hour is achieved. Hospitalization is recommended in refractory cases. Ice packs should be avoided.
A new potential therapy is etilefrine, that has been used successfully in adult patients; however, there are few randomized clinical trials in pediatrics, and no standardized therapeutic options exist.50 Pseudoephedrine may be used for prophylaxis.
Chronic Complications Associated with SCD
Patients with SCD are at risk for many serious chronic complications. Growth failure and delayed puberty are common in children with SCD.51 Skeletal maturation also is delayed.52 Life-threatening infections and CVAs remain a constant threat throughout the lifetime of individuals with SCD. Restrictive and obstructive lung disease, chronic hypoxemia, and pulmonary hypertension with interstitial fibrosis occur in patients with repeated episodes of ACS. Hepatic dysfunction, chronic cholelithiasis, hepatitis C virus infection, transfusion-related hemosiderosis, transfusion-acquired infection, and autoimmune liver disease are additional complications.53
Renal papillary necrosis with renal infarction and microscopic hematuria and hyposthenuria are frequent complications of SCD. Focal glomerulosclerosis can lead to end-stage renal disease. Renal medullary carcinoma is found almost exclusively in African American patients with HbSC disease and in those with sickle cell trait.54-57
Vascular stasis can lead to chronic, nonhealing leg ulcers. Treatment requires meticulous wound care and avoidance of restrictive footwear. Referral to wound care specialists is advisable.
Proliferative retinopathy, retinal detachment, and retinal hemorrhage may begin in early childhood. Acute retinal artery occlusion also is a known complication of SCD.58 Ophthalmology consultation should be included in the routine health care of all patients with SCD. Patients with HbSC disease are at increased risk for developing sickle retinopathy.59
Summary
The myriad of clinical presentations, complications, and life-threatening events that can occur throughout the lives of patients with SCD can prove challenging, even for emergency physicians who routinely treat these patients. The key to effective patient management is rapid recognition and treatment of serious, potentially catastrophic conditions. Aggressive management, appropriate use of analgesia, and consultation with specialists who routinely care for children with this complex disease may result in improved outcomes for children with SCD.
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Patients with sickle cell disease (SCD) frequently present to the emergency department. Life-threatening infections and cerebrovascular accidents remain a constant threat throughout the lifetime of individuals with SCD.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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