Sickle Cell Disease Emergencies in Children
Sickle Cell Disease Emergencies in Children
Authors: Beng R. Fuh, MD, Assistant Professor of Pediatrics, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Brody School of Medicine at East Carolina University, Greenville, NC, and Ronald M. Perkin, MD, MA, Professor, and Chairman, Department of Pediatrics, Brody School of Medicine at East Carolina University, Greenville, NC.
Peer Reviewer: George L. Foltin, MD, FAAP, FACEP, Associate Professor of Pediatric and Emergency Medicine, New York University School of Medicine, New York, NY.
Sickle cell disease is a common condition seen throughout the spectrum of ages. Emergency department (ED) physicians must be aware of the range of presentations and the vulnerability of these patients to certain clinical conditions. Splenic sequestration, acute chest syndrome and strokes are disease processes that cannot be missed in this patient population because of the potential for severe sequelae and long term morbidity and mortality.
Understanding the typical patterns of presentation, initiating appropriate diagnostic and therapeutic interventions may make a tremendous difference in the eventual outcome for these children. Consultation with the child's specialist is also critical to coordinate the acute care, appropriate evaluation, and treatment and, if indicated, transfer to a center skilled in the management of these patients.
The authors review the most common and significant presentations of children with sickle cell disease and the necessary diagnostic and management strategies.
- The Editor
Introduction
Sickle cell disease is one of the most common genetic disorders worldwide. It comprises several hemoglobin (Hb) variants, typically involving the beta globin chain, that lead to chronic hemolytic anemia and several other acute and chronic complications. The most common form in North America is Hb SS; other mutations include Hb SC, Hb S-beta thalassemia, Hb SO Arab, Hb SD, and Hb SE.1 Although affected individuals are usually people of African, Mediterranean, Arab, and Indian ancestry, individuals of other ethnicities may also be affected. The degree of anemia, painful episodes, and organ damage vary widely amongst individuals. The introduction of newborn screening and institution of preventative and new therapeutic measures such as penicillin prophylaxis, chronic transfusions, hydroxyurea, and hematopoietic stem cell transplantation have led to significant improvements in the life span and quality of life of children with sickle cell disease.
Acute sickle cell complications, as shown in Table 1, need prompt management, such as pain relief, to provide patient comfort and to mitigate potential negative sequelae or complications. Appreciating the implications of fever in this population and initiating prompt evaluation decreases the risk of sepsis. Prompt consideration of acute chest syndrome can decrease the likelihood of respiratory failure and long-term cardiopulmonary complications. Timely institution of red blood cell transfusions can decrease the complications associated with cerebral infarcts.
In addition to the immediate management that is necessary in acute emergencies, a comprehensive health care maintenance approach is essential for improving outcomes for children with sickle cell disease. Most children with sickle cell disease are followed at comprehensive sickle cell centers. However, it is not always feasible for them to receive emergent care at such centers, due to distance from the centers and delays in treatment that transportation to such centers may cause. It is therefore essential that emergency medicine physicians be cognizant of and competent in the management modalities available for sickle cell emergencies.
Epidemiology and Etiology
Sickle cell disease was initially described by Dr. James Herrick in 1910 after a student identified the characteristic crescent-shaped cells on a blood smear from a dental student from Grenada.2,3 Years later, it was discovered that individuals with sickle hemoglobin have relative resistance to the malaria parasite; it is thought that the relative resistance of individuals with sickle trait to the malaria parasite provided a survival advantage to these individuals, and thus the propagation of the mutation.4
About 1 in 12 African Americans carries the sickle cell trait, with about 1 in 500 African American newborns having sickle cell disease. Among Hispanics, the incidence of sickle cell disease is about 1 in 1,200 newborns. In some parts of Africa, the prevalence of sickle cell trait is as high as 2 in 5. In the United States, there are about 100,000 individuals living with sickle cell disease, and this number is expected to rise in the next years with improved management of childhood sickle cell disease and increased immigration.2,5 These numbers include both HbSS and HbSC diseases.
Pathophysiology
Hb S and its variants that cause sickling result from point mutations in the beta globin gene. In Hb S, a single point mutation in codon 6, a substitution of thymine for adenine (GAG to GTG), results in the substitution of valine for glutamine in position 6 of the beta globin chain.6,7 The physical properties of the resultant hemoglobin vary significantly from those of wild-type hemoglobin. It tends to form polymers in the deoxygenated state, which causes decreased solubility and molecular stability and eventually leads to several complications associated with sickle cell disease. The formation of hemoglobin polymers leads to gelation of hemoglobin which leads to the deformation of the red blood cell membrane causing the characteristic crescent shaped red blood cells. This phenomenon is called sickling and is initially reversible on oxygenation of hemoglobin, although some cells become irreversibly sickled. Sickled cells loose intracellular potassium and water and become dehydrated.7,8 It has also been shown that sickled cells are deficient in flipase, a membrane protein that is essential in the maintenance of stability of the lipid bilayer of the red blood cell membrane.9
Unlike normal red blood cells, which are easily deformable and able to flow through the microvasculature, sickled red blood cells are rigid and easily get entangled in small blood vessels. This vaso-occlusion is responsible for most of the complications of sickle cell disease; vaso-occlusion causes damage to the endothelium, which enhances platelet activation and the development of a procoagulant state. Also, sickled cells adhere to the endothelium with higher affinity than do non-sickled cells. The process of vaso-occlusion and endothelial damage also induces an inflammatory response.
The cycle of sickling and desickling leads to a drastically decreased lifespan of red blood cells in patients with sickle cell disease, about 20 days compared to 120 days for normal red blood cells. Hemolysis of red blood cells leads to hyperbilirubinemia and bone marrow expansion. Frequent vaso-occlusion in the spleen may initially result in splenic sequestration and eventually auto infarction of the spleen. Children with sickle cell disease also have a compromised immune system.10
These physiological changes result in the following clinical manifestations: Painful vaso-occlusive episodes, hemolytic anemia, splenic sequestration, acute chest syndrome, immune compromise, and multi-organ damage secondary to microinfarcts of the central nervous system (CNS), bones, kidneys, skeleton, penis, and heart.
These complications are more likely in patients with Hb SS than those with Hb SC or other variants of sickling disorders. Conditions that can trigger sickling include infections, dehydration, deoxygenation, acidosis, temperature changes, and emotional stress. Severity and precipitating factors vary significantly between individuals.11
Hb Switching. Fetuses that are homozygous for the sickle cell gene are protected in utero by the presence of Hb F. After birth, the proportion of Hb F progressively decreases and the proportion of Hb S increases. By 6 months of age, these infants overwhelmingly have Hb S, and some may start to manifest significant complications of sickle cell disease.
Complications of Sickle Cell Disease and Their Management
Early Manifestations of Sickle Cell Disease. Dactylitis, or hand-foot syndrome, is one of the early manifestations of vaso-occlusion and can happen as early as 3 months of age. Patients develop characteristic painful swelling of the digits and extremities. The infants have associated irritability and are not easily consolable. Initial treatment focuses on pain control with non-opioid analgesics and supportive care. If pain is not controlled with non-opioid analgesics, opioids should be added. Temperature should be checked prior to administration of medications to assure that the patient is not febrile.7,13
Infections. As early as 6 months of age, children with sickle cell disease have laboratory evidence of abnormal spleen function. As a result, all children with sickle cell disease must be considered immune compromised and treated as such.14 Penicillin prophylaxis is usually initiated as soon as the diagnosis is made. The dosing is 125 mg orally twice daily up to age 3 years; thereafter, the dose is 250 mg orally twice daily until at least 5 years of age. If there is allergy to penicillin, erythromycin will be used. After age 5 years, penicillin prophylaxis may be discontinued as long as the patient has not had a surgical splenectomy or invasive Streptococcus pneumoniae infection.15-17 Children should receive routine childhood immunizations, including the heptavalent conjugated pneumococcal vaccine. At age 2 years, they should also receive the 23-valent polysaccharide pneumococcal vaccine, and receive booster immunizations every five years thereafter. Meningitis immunization is given at puberty, and patients get annual influenza immunizations.
Osteomyelitis is a frequent infection in children with sickle cell disease, with Salmonella being a common pathogen.18 Differentiating osteomyelitis from vaso-occlusive pain can be difficult. Osteomyelitis should be considered if there are significant signs of infection such as fever, extremity warmth, elevated white blood cell count (WBC), and elevated erythrocyte sedimentation rate (ESR). Infection with parvovirus B19 is a frequent cause of aplastic anemia in children with sickle cell disease.19
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Vaso-occlusive Pain. Vaso-occlusive pain can be acute or chronic. A thorough history and physical examination should be performed to make sure pain is secondary to vaso-occlusion and not another etiology such as appendicitis or infection. Pain management should be initiated promptly, as delays unnecessarily prolong discomfort and may complicate the diagnostic evaluation. Fluids and analgesics, including non-opioids and opioids, should be started. Most patients with sickle cell disease are opioid-tolerant, and this should be taken into consideration when initiating pain management with opioids. In many cases, patients may be able to communicate what their usual effective dose is. In general, oral opioids such as oxycodone or morphine can be given together with an oral non-opioid analgesic, such as ibuprofen, at a dose of 10 mg/kg. If adequate pain control is attained, patients may be discharged on scheduled oral analgesics for 24 to 48 hours, then as needed. If there is inadequate pain control, the pain should be treated as moderate to severe pain with parenteral opioids and parenteral or oral non-opioid analgesics. Table 2 shows the management strategies for mild to moderate pain. Hydration can be started orally prior to the establishment of IV access. If IV fluids are started, a normal saline bolus should be given, followed by IV fluids at a rate of one to one-and-one-half times maintenance. If acute chest syndrome is suspected, IV fluids should be limited to no more than maintenance, as this may cause pulmonary edema and worsen acute chest syndrome. A temperature should be checked to ascertain that there is no fever. Most patients with sickle cell disease have analgesics at home, and pain management may have been attempted prior to presentation to the ED. If the patient has failed management with oral analgesics and is in the ED or being admitted, patient-controlled analgesia (PCA) should be considered.
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Acute Chest Syndrome. Acute chest syndrome is an acute lower respiratory tract illness associated with a new or progressive pulmonary infiltrate on chest x-ray and fever or chest pain, tachypnea, wheezing, hypoxia, or increased sputum production. Acute chest syndrome is one of the leading causes of hospitalization in children with sickle cell disease. It is also a frequent treatment-related complication, especially post surgery. In one study, 50% of children who developed acute chest syndrome did so in the hospital while admitted for other complaints with no respiratory symptoms. About half of all individuals with sickle cell disease will experience at least one episode of acute chest syndrome in their lifetime. The etiology of acute chest syndrome remains unclear. In one study, infections accounted for 29% of cases. A cause was identified in only 38% of cases.24,25
Acute chest syndrome must be diagnosed and treated promptly to limit complications and long-term sequelae. Evaluation should include a CBC with differential, reticulocyte count, blood cultures, and chest x-ray. Laboratory evaluation of blood gases, blood chemistries, renal functions, and liver enzymes should be considered. Treatment is multimodal and comprises broad-spectrum antibiotics, including a cephalosporin and a macrolide, to cover for typical and atypical microorganisms. Vancomycin should be considered for ill-appearing children. Simple or exchange transfusion should be given if there is multilobar disease, progressive infiltrate, hypoxia beyond baseline, history of prior acute chest syndrome, or otherwise ill appearance.20 The target hemoglobin is 10 g/dL and not to exceed 12 g/dL and a Hb S concentration less than 30%. Transfused blood should be sickle-negative, leukoreduced, and if possible, major and minor antigen matched. The goal of hydration should be euvolemia, with caution taken to avoid fluid overload. If there are signs of fluid overload, furosemide should be considered.
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Supplemental oxygen should be given to keep pulse oximetry greater than 91% or at baseline. Any increased oxygen requirement should prompt a reassessment, since patients with acute chest syndrome can worsen precipitously. Also consider bronchodilators, since up to 80% of patients with acute chest syndrome develop bronchospasm.24 Pain should be treated accordingly with opioids and non-opioids.
All patients with acute chest syndrome should have incentive spirometry and early ambulation.
It is important to frequently reassess all patients with sickle cell disease to determine the effect of interventions and detect possible deteriorations early on. Consider intensive care management and ventilator support with respiratory deteriorations, including inhaled nitric oxide as needed. Figure 2 demonstrates how acute chest syndrome can worsen over a short timeframe.
Acute Splenic Sequestration. Children with sickle cell disease can develop an acute intrasplenic trapping of red blood cells, leading to a significant decrease in hemoglobin from baseline. The peak incidence is between the ages of 2 years and 5 years, with the incidence of splenic sequestration decreasing by age 3 years because of progressive autosplenectomy. Children with sickle cell SC disease and other variants, as well as children with sickle cell SS disease and early institution of chronic transfusions, may have splenic sequestration all the way into adult life. Children with splenic sequestration develop a reticulocytosis, which differentiates it from aplastic anemia. There may also be an associated thrombocytopenia and/or leukopenia. Splenic sequestration is frequently induced by an infection.26
Splenic sequestration is critical to consider because hypovolemic circulatory collapse can occur rapidly. Diagnostic evaluation and treatment should include close monitoring of vital signs, CBC with reticulocyte count and a type and screen for possible transfusion. Blood cultures should be obtained, and antibiotics initiated if any concern for infection exists. Emergent management should include volume expansion with normal saline boluses or lactated Ringer's solution while awaiting CBC results to initiate transfusion. Target hemoglobin should not exceed 10 mg/dL, as there is a risk of trapped intrasplenic red blood cells being released into the circulation and leading to hyperviscosity. Consider intensive care management if there is cardiopulmonary compromise. Splenectomy should be considered in children with more than two episodes of splenic sequestration. Children status post surgical splenectomy should be placed on lifelong penicillin prophylaxis.
Aplastic Anemia. Transient red blood cell aplasia is a common finding in children with sickle cell disease; the children usually present with a decrease in hemoglobin from baseline without an associated increase in reticulocyte count. Anemia results from continuing hemolysis with no adequate replacement of red blood cells by the bone marrow. Several viruses and bacteria can cause aplastic anemia. Parvovirus B19, the most common cause of aplastic anemia in children with sickle cell disease, may also induce splenic sequestration.20,27,28 Although a low reticulocyte count typically differentiates aplastic anemia from splenic sequestration, there may be concurrent occurrence of splenic sequestration and aplastic anemia, in which case splenomegaly may be present.
Evaluation should include a thorough physical examination with close monitoring of vital signs, a complete blood count with reticulocyte count and type and screen for possible transfusion. Blood culture should be done and antibiotics started if there is a concern for infection.
Aplastic anemia in children with sickle cell disease is usually self-limited and requires only close monitoring. Patients with severe anemia (hemoglobin < 5g/dL) or who are symptomatic should be transfused. If anemia persists for a long period, treatment with erythropoietin and IV immunoglobulin (IVIG) may be considered.
Patients with parvovirus B19 develop lifelong immunity. Individuals of child-bearing age should take precautions around children with parvovirus B 19 infection, since the virus can cause birth defects in pregnant females.
Neurologic Complications. An acute, clinically apparent neurological event occurs in about 10% of children with sickle cell disease. A stroke may occur as an isolated event or may occur as a complication of another complication of sickle cell disease, such as acute chest syndrome, splenic sequestration, or aplastic anemia. The rate of blood flow in the middle cerebral and the anterior cerebral arteries, as measured by transcranial doppler ultrasonography, has been shown to be a good predictor of the risk of stroke. Common presenting signs and symptoms of stroke include hemiparesis, aphasia or dysphasia, monoparesis, seizures, cranial nerve palsies, headache, stupor, or coma. Any child with sickle cell disease and a neurologic event should be evaluated and treated promptly. A high index of suspicion for strokes in children with sickle cell disease is critical, otherwise subtle signs of stroke may be missed. In addition to overt strokes, children with sickle cell disease may develop silent cerebral infarcts. In these children, there is radiographic evidence of stroke with no corresponding clinical findings. Most overt strokes in children are ischemic or thrombotic in nature.
Evaluation should include a CBC, reticulocyte count, hemoglobin electrophoresis, and type and cross-match for red blood cell transfusion. Imaging should include magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) of the brain. Frequently, MRI cannot be performed in emergency situations, and a computed tomography (CT) scan should be obtained initially. When a stroke is suspected in a child with sickle cell disease, a simple transfusion or exchange transfusion should be initiated as soon as possible.29-33 Blood transfusions should not be delayed for imaging.
Chronic transfusion is the only therapy that has been proven to decrease the risk of stroke recurrence in children with sickle cell disease.20 If a stroke is confirmed on imaging, chronic transfusions should be instituted to suppress hematopoiesis and keep the proportion of Hb S less than 30%. Children with transcranial doppler flow velocities of greater than 200 cm/s are considered to be at high risk of stroke and should be treated with chronic transfusions. Chronic transfusions are frequently associated with the complication of iron overload, which, if not appropriately managed, can lead to multi-organ complications. Hydroxyurea is currently being investigated as a possible alternative treatment.
The significance of silent cerebral infarcts is still unclear and is currently being investigated. It is suspected that silent infarcts increase the risk of overt stroke and may cause cognitive and behavioral problems. It is unclear if chronic transfusions are necessary or beneficial in children with silent infarcts.
Priapism. Priapism is a prolonged and painful erection of the penis that may occur in children with sickle cell disease. It can be severe and persistent, lasting more than four hours, or it may be stuttering, lasting less than four hours but recurrent. Sometimes, stuttering priapism follows prolonged priapism. Simple and brief episodes of priapism can be managed with increased fluid intake, analgesics, exercise, urination, or showering. Priapism lasting more than four hours is an emergency and should be evaluated and treated promptly, because delayed treatment increases the risk of impotence. Evaluation should include a CBC and reticulocyte count. Corporal aspiration and irrigation with epinephrine should be performed. If priapism lasts more than 12 hours, transfusion should be considered, and if priapism lasts more than 24 hours, a winter shunt (shunt between corpora cavernosa and the glans penis) should be considered.20,34 Patients with recurrent priapism should be considered for prophylactic ephedrine daily or androgen blockade.
Chronic Complications of Sickle Cell Disease in Children
Improvements in the management of acute complications of sickle cell disease have led to increased survival and increased life span. This has increased the prevalence of chronic complications, especially in adolescents and adults, and these diagnoses should be considered in a patient with the appropriate presentation.
Osteonecrosis of the Femoral Head. Osteonecrosis of the femoral head can occur in up to 50% of patients with sickle cell disease by 35 years of age. It can cause debilitating chronic pain and is a frequent cause of disability in patients with sickle cell disease. Treatment with analgesics, physical therapy, and coring procedures may be considered.
Pulmonary Hypertension. One serious chronic complication is pulmonary artery hypertension, with pulmonary artery pressure greater than 25 mmHg, which may occur in up to 30% of adolescents. In its initial phase, pulmonary hypertension is asymptomatic, but eventually results in dyspnea and hypoxia, and is a frequent cause of death. The etiology of pulmonary hypertension has not been well defined, but it is suggested that altered nitric oxide bioavailability secondary to chronic hemolysis plays a major role in the pathophysiology. Treatment options are limited, but there are current experimental treatments that interact with the nitric oxide bioavailability being explored.35-37
Gallstones. Gallstones develop secondary to chronic hemolysis in patients with sickle cell disease. Gallstones may manifest as right upper quadrant pain, postprandial nausea, or emesis. If gallstones are symptomatic, a cholecystectomy should be considered.
Ulcers. Children with sickle cell disease can develop skin ulcers that, when not adequately managed, can become very difficult to heal and lead to amputations. Children with sickle cell disease require good foot hygiene, and injuries should be managed promptly. Patients developing skin ulcers should be managed with wet to dry dressing, antibiotic and analgesics as needed, and surgical debridement should be considered where appropriate. Physical therapy may be useful.
Other chronic complications of sickle cell disease include retinopathy, renal complications, cardiac complications, obstetric complications, and self-image problems.
Therapies in Sickle Cell Disease
Transfusion Therapy. Children with sickle cell disease frequently require red blood cell transfusions transiently to treat acute complications of the disease. Clinical situations that may warrant red blood cell transfusions include aplastic anemia, splenic sequestration, acute chest syndrome, and presurgically for most surgical procedures. The goal of presurgical transfusions is a hemoglobin of 10 g/dL. It is not necessary to decrease the proportion of Hb S to less than 30%. Conditions requiring chronic or exchange transfusions include patients with clinical stroke and those with abnormal tanscranial doppler ultrasonography findings. Children with sickle cell disease should be transfused packed red blood cells that are sickle negative, leukoreduced, ABO as well as C, D, E, and Kell matched.38 Though an important tool in the management of sickle cell disease, transfusions should be used judiciously. Complications of blood transfusions include acute febrile reactions, potential infection, alloimmunizations, among others. Chronic transfusions can lead to iron overload that, if not well managed, can cause several complications, including cirrhosis, cardiomyopathy, and diabetes. Children receiving chronic transfusions should be monitored for iron overload, and if found to be iron overloaded should be treated with iron chelators such as deferasirox (oral) or deferoxamine (parenteral). Hemoglobin concentrations greater than 12 g/dL should be avoided, as this can lead to hyperviscosity and increased risk of stroke.
Hydroxyurea. Hydroxyurea is a cytotoxic agent that has been shown to increase the proportion of hemoglobin F and decrease the leukocyte, platelet, and reticulocyte counts in patients with sickle cell disease. It has been shown to decrease the frequency and severity of vaso-occlusive pain episodes, acute chest syndrome, and the need for transfusions. It is currently being studied for possible benefits in patients with strokes as an alternative to chronic transfusions.
Nitric Oxide. Hemolysis induces relative deficiency of nitric oxide via the reaction of hemoglobin with endothelial nitric oxide and the inhibition of nitric oxide synthesis by arginase. This leads to the chronic vasoconstriction and activation of hemostasis, with consequences such as pulmonary hypertension, priapism, stroke, and ulcers. Inhaled nitric oxide reacts with free hemoglobin to form methemoglobin, thereby freeing up endogenous nitric oxide to provide vascular relaxation and improve vasculopathy. Studies are ongoing to determine the effectiveness of nitric acid in preventing or improving sickle cell vasculopathy. Arginine is being studied as a substrate for arginase in an attempt to increase endogenous nitric oxide synthesis.37,39 Several other approaches that aim to increase endogenous nitric oxide are being studied and offer hope for new therapies in the near future.
Hematopoietic Stem Cell Transplantation. Hematopoietic stem cell transplantation represents the only possible cure for sickle cell disease. However, given the risk of transplantation, only a selective risk group of patients are considered for transplantation. These include patients with a history of strokes, abnormal transcranial doppler ultrasonography, or severe recurrent episodes of acute chest syndrome. The best donors are matched siblings. Recently hematopoietic stem cell transplantation utilizing cord blood and non-sibling donors have been explored.40,41
Conclusion
Sickle cell disease remains one of the most common hereditary diseases in the world, with potential severe acute and chronic complications. Patients with sickle cell disease require close medical management to avoid complications, and when complications develop they should be diagnosed and managed promptly and appropriately. Patients presenting with sickle cell complications should be evaluated in a timely manner and reassessed frequently to avoid deterioration and long-term sequelae. Fever should be considered a sign of potential serious infection and treated with parenteral antibiotics. Pain should be managed with a combination of opioid and non-opioid analgesics with the goal of timely pain relief. Patients should also have oral opioid and non-opioid analgesics available at home for prompt self-management of pain. Acute chest syndrome is a serious complication and cannot be easily differentiated from pneumonia. It requires prompt multi-modal management and close clinical monitoring. Clinicians should have a high index of suspicion for stroke, and if stroke is suspected, red blood cell transfusions should be initiated as soon as possible. Splenic sequestration can lead to hypovolemic shock, and fluid resuscitation must be immediately instituted pending the availability of packed red blood cells. Management of sickle cell complications should be done in coordination with the pediatric hematologist. The introduction of newborn screening and other recent advances have led to a significant improvement in the quality of life and life expectancy for patients with this condition. The development of small molecules, gene therapy, and improvement in hematopoietic stem cell transplantation modalities hold reasonable hope for cures in the future.
References
1. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (Hb S) allele and sickle cell disease: A HuGE review. Am J Epidemiol 2000:151: 839-845.
5. National Heart, Lung and Blood Institute (NHLBI). Sickle cell anemia. NIH Publication No. 96-4057, 1996. Available at: www.nhlbi.nih.gov/health/public/blood/sickle/sca_fact.txt. (Accessed Nov. 11, 2009.)
2. Ranney HM. Historical milestones. In: Embury SH, Hebbel RP, Mohandas N, et al., Eds. Sickle Cell Disease Basic Principles and Clinical Practice. New York:Raven Press;1994:1-5.
3 A Brief History of Sickle Cell Disease. Joint Center for Sickle Cell and Thalassemic Disorders. Brigham and Women's Hospital, Boston:2005. Available at http://sickle.bwh.harvard.edu/menu_sickle.html. (Accessed Nov. 11, 2009.)
4. Friedman MJ. Erythrocytic mechanism of sickle cell resistance to malaria. Proc Natl Acad Sci USA 1978;75:1994-1997.
6. Clancy S. Genetic mutation. A single base change can create a devastating genetic disorder or a beneficial adaptation, or it might have no effect. How do mutations happen, and how do they influence the future of a species? Nature Education 2008:1:729-742.
7. Steinberg MH. Sickle cell disease and associated hemoglobinopathies. In: Goldman L, Ausiello D, et al., Eds. Cecil Medicine: Expert Consult, 23rd ed. Philadelphia: WB Saunders; 2008: 1217-1226.
8. Dover GJ, Platt OS. Sickle cell disease. In: Nathan DG, Orkin SH, et al. Nathan and Oski's Hematology of Infancy and Childhood, 5th ed. Philadelphia: WB Sauders; 1998:790-841.
9. Murayama M. A molecular mechanism of sickled erythrocyte formation. Nature 2002:258-260.
10. Banerjee T, Kuypers FA. Reactive oxygen species and phosphatidylserine externalization in murine sickle red cells. Br J Haematol 2004:124:391-402.
11. Steinberg MH. Sickle cell anemia, the first molecular disease: Overview of molecular etiology, pathophysiology, and therapeutic approaches. ScientificWorldJournal 2008:25:1295-1324.
12. Davis SC. The Vaso-occlusive crisis of sickle cell disease. BMJ 1991: 302:1551-1552.
13. Brugnara C, Platt OS. The neonatal erythrocyte and its disoders. In: Nathan DG, Orkin SH, et al. Nathan and Oski's Hematology of Infancy and Childhood, 5th ed. Philadelphia: WB Sauders; 1998: 19-54.
14. Worrall VT, Butera V. Sickle-cell dactylitis. J Bone Joint Surg Am 1976: 58:1161-1163.
15. Casper JT, Koethe S, Rodey GE, et al. A new method for studying splenic reticuloendothelial dysfunction in sickle cell disease patients and its clinical application: A brief report. Blood 1976:47:183-188.
16. Powars D, Overturf G, Weiss J, et al. Pneumococcal septicemia in children with sickle cell anemia: Changing trend of survival. JAMA 1981:245:1839-1842.
17. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986:19;314:1593-1599.
18. Falleta JM, Woods GM, Verter JI, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia. J Pediatr 1995;127: 685-690.
19. Berger E, Saunders N, Wang S, et al. Sickle cell disease in children. differentiating osteomyelitis from vaso-occlusive crisis. Arch Pediatr Adolesc Med 2009;163:251-255.
20. Smith-Whitley K, Zhao H, Hodinka RL, et al. Epidemiology of human parvovirus B19 in children with sickle cell disease. Blood 2004:103:251-255.
21. National Heart, Lung and Blood Institute (NHLBI). The management of Sickle Cell Disease. NIH Publication No. 02-2117, 2002. Available at: www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf. (Accessed Nov. 11, 2009.)
22. Evans E, Turley N, Robinson N, et al. Randomised controlled trial of patient controlled analgesia compared with nurse delivered analgesia in an emergency department. Emerg Med J 2005;22:1.
23. Van beers EJ, Van Tuijn CF, Nieuwkerk PT et al. Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease: A randomized controlled trial. Am J Hematol 2007:82:955-960.
24. Buchanan ID, Woodward M, Reed GW. Opioid selection during sickle cell pain crisis and its impact on the development of acute chest syndrome. Pediatr Blood Cancer 2005:45:716-724.
25. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med 2000;342:1855-1865.
26. Golden C, Styles L, Vichinsky E. Acute chest syndrome and sickle cell disease. Curr Opin Hematol 1998:5:89-92.
27. Topley JM, Rogers DW, Stevens MC. Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 1981:56:765-769.
28. Adler SP, Manganello AM, Koch WC. Risk of human parvovirus B19 infections among school and hospital employees during endemic periods. J Infect Dis 1993;168:361-368.
29. Miller S, Macklin E, Pegelow C, et al. Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: A report from the Cooperative Study of Sickle Cell Disease. J Pediatr 2001:139: 385-390.
30. Ohene Frempong K, Weiner SJ, Sleeper LA et al. Cerebrovascular accidents in sickle cell disease: Rates and risk factors. Blood 1998: 91:288-294.
31. Driscoll CM. Sickle cell disease. Pediatr Rev 2007:28:259-268.
32. Lee MT, Piomelli S, Miller ST, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): Extended follow-up and final results. Blood 2006:108:847-852.
33. Adams RJ, Mckie VC, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998:339:5-11.
34. Mantadakis E, Ewalt DH, Cavender ZR, et al. Outpatient penile aspiration and epinephrine irrigation for young patients with sickle cell anemia and prolonged priapism. Blood 2000:95:78-82.
35. Belcher JD, Beckman JD, BallaG, et al. Heme degradation and vascular injury. Antioxid Redox Signal 2009. (Epub ahead of print.)
36. Kato GJ, Hebbel RP, Steinberg MH, et al. Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions. Am J Hematol 2009;84:618-625.
37. Kato GJ, Gladwin MT. Evolution of novel small-molecule therapeutics targeting sickle cell vasculopathy. JAMA 2008:300:2638-2646.
38. Castro O, Sandler SG, Houston Y. Predicting the effect of transfusing only phenotype-matched RBCs to patients with sickle cell disease: Theoretical and practical implications. Transfusion 2002:42:684-690.
39. Mack KA, Kato GJ. Sickle cell disease and nitric oxide: A paradigm shift? Inter J Biochem Cell Biol 2006:38:1237-1243.
40. Walters MC. Cord blood transplantation for sickle cell anemia: Bust or boom? Pediatr Transplant 2007:11:582.
41. Mazur M, Kurtzberg J, Halperin E, et al. Transplantation of a child with sickle cell anemia with an unrelated cord blood unit after reduced intensity conditioning. J Pediatr Hematol Oncol 2006;28:840-844.
Sickle cell disease is a common condition seen throughout the spectrum of ages. Emergency department (ED) physicians must be aware of the range of presentations and the vulnerability of these patients to certain clinical conditions.Subscribe Now for Access
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