AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Sickle cell disease is an inherited disorder of hemoglobin synthesis. The resulting abnormality produces a normocytic, hemolytic anemia with multiple diversely shaped RBCs that are susceptible to morphologically changing into a sickle shape. The sickle cells produce thrombosis and obstruction in small vessels, leading to ischemia and necrosis of distal tissue.

Pathophysiology

Sickle cell disease results from a single amino acid substitution (valine for glutamate) in position 6 of the beta-globin chain of hemoglobin. This genetic alteration yields an unstable RBC with a shortened survival that under stress becomes sickle shaped.

Frequency

United States

Approximately 8-10% of African Americans in the population carry the gene S. Homozygous (SS) sickle disease occurs in about 0.15% of African American newborns.

International

Other sickle syndromes may be present in individuals from India, the Middle East, and the Mediterranean.

Mortality/Morbidity

The clinical course of sickle cell disease is one of chronic illness precipitated by multiple acute exacerbations that can become life threatening at any time.

• Today, approximately 50% of patients survive beyond the fifth decade.
• A third of deaths during an acute crisis occur in patients who are clinically free of organ failure.
• Infection is the leading cause of death in affected children aged 1-3 years.
• Strokes and trauma are the leading causes of death in patients aged 10-20 years. Children in this age range also die from acute chest syndrome, splenic sequestration crisis, and aplastic crisis.

Race

Sickle hemoglobinopathy syndromes are genetically predetermined hemolytic anemias that predominantly occur in individuals of Central African descent. In Latin America, high frequencies are observed in the Caribbean, Guyanese, Panamanian, and Brazilian populations.

Age

• Hematologic changes indicative of the disorder are evident as early as the age of 10 weeks, though symptoms are usually delayed until the age of 6-12 months because of high levels of circulating fetal hemoglobin.
• Beta-chain (adult) hemoglobulin is usually not prominent until the age of 3 months.
• After infancy, erythrocytes of patients with sickle cell anemia contain approximately 90% hemoglobin S (HbS), 2-10% hemoglobin F (HbF), a normal amount of minor fraction of adult hemoglobin (HbA2), and no hemoglobin A (HbA).

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

Patients with sickle cell disease, at some point in their lifetime, may experience exacerbations in their clinical course. Children at different ages are susceptible to differing types of crisis, which each may occur in a given child at some point.

• A painful vaso-occlusive crisis is the most frequent clinical symptom of sickle cell disease.
• • In infants, painful symmetrical swelling of the hands and feet (dactylitis or hand-foot syndrome) caused by infarctions of the small bones may be the initial manifestation of sickle cell anemia.
  • Most bony vaso-occlusive events occur primarily in the bone marrow cavity. Most are multifocal and associated with mild tenderness and localized edema.
  • As the child matures, the painful episodes usually affect the joints, especially the hips and knees and those of the chest wall and back. Document the frequency, the precipitants, and the similarity of painful episodes on each visit to exclude more serious causes, such as infection.
• Promptly evaluate older patients who complain of chest pain, cough, dyspnea, or tachypnea to exclude acute chest syndrome.
• • The acute febrile pneumonic process is associated with new infiltrates on chest radiographs. Chest pain may precede the radiographic findings, or they may occur with the onset of pain. Although initial chest radiographs may be normal, subsequent radiographs reveal an infiltrate, which may rapidly extend to involve 1 or more lobes and the pleura.
  • The etiology may be infectious (eg, pneumonia), vaso-occlusive, or both. This syndrome often results in hypoxia and, occasionally, death.
• Abdominal pain often occurs as excruciating pain with diffuse tenderness, distension, and muscular rigidity of the abdominal wall.
• • The pain often is caused by small infarcts of the mesentery and viscera, usually without peritoneal signs.
  • A thorough history, obtained from the patient or the parents, is crucial because their recognition of the nature of the pain helps in distinguishing vaso-occlusive pain from that of other etiologies, such as cholecystitis, perforated viscus, or appendicitis.
• Sequestration crisis is a distinct form of acute hypersplenism unique to infants and young children.
• • Vascular occlusion occurs in the splenic sinusoids, resulting in large volumes of blood trapped in the substance of the spleen.
  • If these events occur gradually, the patient may present with progressive pallor, fatigue, left-sided abdominal pain, and increasing splenomegaly.
  • This event may occur before or after autoinfarction of the spleen transpires. If splenic sequestration occurs more abruptly, patients may present in extremis, manifesting severe hypovolemic shock.
• If vascular occlusion occurs in large or small cerebral vessels, a neurologic event may occur.
  • Patients may have gait disturbances, hemipareses, paresthesias, aphasias, altered consciousness, or seizures.
  • MRI findings or high flow on transcranial Doppler sonography of silent lesions are associated with a high risk of stroke.
• Men may present with priapism (ie, prolonged, acute, and painful erection due to venous occlusion). Priapism may recur often.
• Infants and children are susceptible to aplastic anemia crisis.
• • During episodes of crisis, the degree of anemia worsens, and jaundice decreases due to a profound reticulocytopenia, resulting in no erythrocyte precursors in the bone marrow.
  • The patient appears acutely ill, tachycardic, and pale, yet nonicteric.
  • Occasionally, patients recover in several days.
  • The symptoms are usually due to an infection by the parvovirus B19 prototype.
• Patients with sickle trait have erythrocytes that contain only 30-40% HbS. Heterozygosity for the sickle gene has a benign clinical course. Sickling does not occur under physiologic conditions.
  • In rare cases, patients may have hypoxia or shock when flying at high altitudes in an unpressurized aircraft, which causes vaso-occlusive phenomena.
  • Spontaneous hematuria, usually from the left kidney, has also occurred in patients with the sickle trait. The bleeding is often mild, but blood transfusion is often needed.
  • Patients with sickle cell disease and trait often have a high incidence of enuresis because their bodies cannot appropriately concentrate urine.

Physical

In evaluating the patient with sickle cell disease, it is important to consider the pattern of past events, baseline laboratory values, and current status of disease.

• Patients most often present with pain complaints; but younger children, who cannot communicate well, must be observed for irritability, poor feeding, or fussiness.
• Vital signs must be evaluated for fever, tachycardia, and tachypnea, which may be present due to pain or infection.
• As the patient matures, he or she may have icteric sclera and pallor of the conjunctiva and mucous membranes. Funduscopic examination may reveal retinopathy.
• • Dental malocclusion may be present secondary to maxillary hyperplasia due to expansion of the bone-marrow space.
  • Perform cardiac examination to determine presence of a murmur.
  • Auscultation rales, or breath sounds may be decreased bilaterally due to extensive pulmonary consolidation. Infarction is difficult to distinguish from pneumonia.
• The presence of active bowel sounds, absence of emesis, and patient recognition of pain helps distinguish vaso-occlusive pain from other etiologies.
• • Abdominal examination of the young child may reveal splenomegaly if sequestration is occurring. Otherwise, the spleen recedes and should not be palpable by the age of 3-4 years as a result of autoinfarction.
  • In patients with mild variants of sickle disease, splenomegaly may persist into adulthood.
  • Note the size of the liver and examine for evidence of gallstones, as these can form in patients as young as 3 years.
• Inspect the genitalia for priapism if the patient complains of pain.
• The most dramatic physical finding often is observed in the extremities.
• • Young infants may have recurrent edema of the dorsum of the hands and feet.
  • Infarction of the cortex of the long bones may lead to prominent signs of local inflammation, including tenderness, edema, and erythema.
  • As the child grows, repetitive infarctions in the joints of large and small bones may produce abnormally angled digits and enlarged, malformed, and (occasionally) frozen joints, particularly at the knees and ankles.
  • Chronic leg ulcers are common in the adolescent patient.
• Thoroughly examine any patient who complains of mental status changes, paresis, or other symptoms compatible with a stroke because strokes are prominent in this age group.
• By mid childhood, most patients are underweight compared with children of their same age and height.

Causes

• The sickling process that frequently occurs with sickle cell anemia may be precipitated by multiple factors.
• • A crisis may be induced by local tissue hypoxia, dehydration secondary to a viral illness, or nausea and vomiting, all of which lead to hypertonicity of the plasma.
  • Any process that can lead to acidosis, such as infection or extreme dehydration, can cause sickling.
  • More benign factors and environmental changes, such as fatigue, exposure to cold, and psychosocial stress, can elicit the sickling process that prompts a crisis.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Sickle cell hemoglobin
Thalassemia

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Newborn screening for sickle hemoglobinopathies is mandatory in 43 states. Therefore, most patients presenting to the ED have a known diagnosis.
• Specific diagnosis is confirmed with hemoglobin electrophoresis performed in specialized reference laboratories.
• The patient with homozygous sickle cell disease typically has a hemoglobin level of 5-9 g/dL, with a hematocrit level decreased to 17-29%.
• The total leukocyte count is elevated to 12,000-20,000 cells/mm³ (12-20 X 10⁹/L), with a predominance of neutrophils.
• The platelet count is increased, and the sedimentation rate is low.
• The reticulocyte count is usually elevated, but it may vary depending on the extent of baseline hemolysis.
• Peripheral blood smears demonstrate target cells, elongated cells, and characteristic sickle erythrocytes.
• Results of hemoglobin solubility testing are positive, but they do not distinguish between sickle cell disease and sickle cell trait.
• Perform the following laboratory studies in patients younger than 5 years who presents with a temperature >38.5°C:
• • Tests for liver enzyme levels
  • Tests for electrolyte levels
  • Determination of complete blood count (CBC) with differential
  • Determination of the reticulocyte count
  • Urinalysis
  • Blood, urine, and throat cultures
• During bacterial infection, elevations of the absolute band count to more than 1000/mm³ are common compared to moderate elevations during the painful crisis.
• Laboratory studies for the patient presenting with a painful crisis should routinely include determination of the CBC and reticulocyte counts for comparison with counts from previous episodes.
• During the vaso-occlusive crisis, the reticulocyte count may rise to 30%.
• Perform blood gas analysis if pulmonary symptoms exist.

Imaging Studies

• In patients with cough or chest pain, prompt chest radiography is warranted to differentiate pneumonia versus acute chest syndrome.
• If an ill-appearing patient presents with pain in the extremities that differs from his or her usual painful episodes, radiography and/or MRI of the affected extremity is necessary to exclude osteomyelitis.
• Evaluate any new onset of neurologic changes by performing head CT or brain MRI to exclude a stroke.

Other Tests

• Use a pulse oximeter on the patient complaining of chest pain to assess hypoxia related to acute chest syndrome.

Procedures

• Consider lumbar puncture in the pediatric patient with altered mental status, meningeal signs, and fever to exclude meningitis.
• Also perform lumbar puncture if a subarachnoid hemorrhage is suspected if head CT reveals no evidence of increased intracranial pressure or mass lesion.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Emergency Department Care

The emergency physician must weigh all etiologies of possible precipitants when evaluating the presumed painful crisis.

• In the ED, the mainstay of therapy for vaso-occlusive crises is hydration and analgesia.
• Hydration should be administered to replace ongoing losses and meet maintenance needs, as well as correct preexisting deficits. Administer intravenous (IV) isotonic sodium chloride solution at a rate of 1-1.5 times the maintenance rate if oral hydration cannot be sustained.
• Base analgesia on the severity of symptoms and the response to therapy at home before the patient's presentation in the ED.
• • Mild pain can be controlled by giving ibuprofen or acetaminophen (with or without codeine).
  • If pain is more severe, patients can be given morphine, meperidine, hydromorphone, or oxycodone. Some pediatric patients have benefited from high-dose IV methylprednisolone. Ketorolac may also be considered. It is a potent NSAID indicated for <5-d management of moderately severe acute pain that requires analgesia at opioid level.
• Patients presenting with variable signs of respiratory distress suggestive of acute chest syndrome should be given early and aggressive therapy. Fluids should be monitored judiciously to avoid pulmonary edema. Use of an incentive spirometer may prove helpful.
• • Antibiotic therapy should cover Pneumococcus species, Haemophilus influenzae type b, and Mycoplasma pneumoniae, with drugs such as cefuroxime, ceftriaxone, and erythromycin, respectively.
  • Provide oxygen and respiratory support to relieve hypoxemia.
  • When respiratory distress is moderate to severe, especially with progressive anemia, transfusion is appropriate to increase the oxygen-carrying capacity and to decrease the percentage of sickle hemoglobin, thereby diminishing the tendency for intrapulmonary vaso-occlusion.
• For the patient with acute splenic sequestration, therapy is primarily directed at restoring intravascular volume with appropriate isotonic fluids. Severe anemia requires transfusion therapy. The size of the spleen tends to return to its baseline state with an associated increase in hemoglobin concentration over several days.
• Patients with suspected stroke require immediate exchange transfusion sufficient to decrease the percent of sickle hemoglobin to less than approximately 25%.
  • A single volume-exchange transfusion of packed RBCs, reconstituted with fresh-frozen plasma (FFP), to a hematocrit of approximately 40% is an appropriate emergency measure.
  • If the patient has occlusive disease of the large vessels, long-term transfusion therapy is required to prevent recurrent stroke.
  • If signs of increased intracranial pressure develop, hyperventilation is warranted, as are anticonvulsants to control seizure activity.
• Treat priapism with analgesia, hydration, and transfusion therapy sufficient to decrease the sickle hemoglobin level to less than 30%.
  • The choice between a simple RBC transfusion and exchange transfusion depends on the initial hematocrit.
  • This level should not be increased above 35% to avoid hyperviscosity and an increased tendency for sickling.
• Transfusions may be necessary for the patient with aplastic crisis, though the condition often spontaneously resolves within 5-10 days.
  • Caution should be exercised to isolate the child at the time of aplasia, because the human parvovirus B19 is responsible for more than 80% of crises and highly contagious.
  • The patient should be isolated from all vulnerable groups, such as immunocompromised children, children with hemolytic anemia, and pregnant women.

Consultations

• Always call the patient's primary pediatrician if the patient presents with severe complications of his or her sickle cell disease.
• Consult a pediatric hematologist for any patient requiring an exchange transfusion as therapy for their disease process.
• If the patient presents with neurological deficits, a pediatric neurologist may be consulted after the initial evaluation and workup.
• Multiple pediatric tertiary care centers equipped with specialized sickle cell services have emerged over the last few years. Children with sickle cell disease who become acutely ill may best be served by these facilities.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Drug Category: Analgesics

Medications used selectively for analgesia should be chosen based on the severity of pain. Maximum doses and frequencies of administration should be used for milder medications prior to using stronger pain medications.

Drug Category: Cytoreductive agent

Increases production of fetal hemoglobin.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• The primary care team should reevaluate the medication plan every day for patients admitted for pain control.
• • Taper IV drug doses when acute pain subsides, but do not change the dosing interval.
  • Once the patient tolerates a 50% decrease, consider oral analgesics and discontinue parenteral therapy.
• If IV antibiotics were started in the ED, continue therapy until appropriate culture results suggest a possible change in antibiotic choice.
• In patients who required emergency transfusion, hematocrits should be checked to ensure adequacy of the transfusion.
• The primary care team should review the patient's immunization schedule and prophylactic antibiotic therapy.

Further Outpatient Care

• The patient's pediatrician should examine the patient every 3-4 months to review their acute illnesses and possible precipitants and the frequency of crises, hospitalizations, and blood transfusions.
• The patient's CBC, reticulocyte count, liver function, and renal function should be monitored during these follow-up visits.
• In addition to the immunization schedule currently recommended by the American Academy of Pediatrics, pediatric patients with sickle cell disease require pneumococcal, meningococcal, and influenzal vaccines.
• • The pneumococcal vaccine should be administered at age 2 years with subsequent boosters determined by the patient's hematologist.
  • Meningococcal prophylaxis is administered as a single quadrivalent vaccine when the child is older than 2 years.
  • The influenza vaccine is administered annually.

In/Out Patient Meds

• Penicillin prophylaxis for encapsulated organisms is instituted as soon as the diagnosis of sickle cell disease is established, preferably by the age of 2 months.
• • An initial dose of penicillin V or G 125 mg twice daily (bid) is recommended.
  • The dose is increased to 250 mg bid by age 3 years.
  • If the patient is allergic to penicillin, erythromycin may be substituted.
• The pediatrician initiates folic acid therapy.
• • For patients younger than 6 months, the usual dose is 0.1 mg/d.
  • For infants aged 6 months to 1 year, the usual dose is 0.25 mg/d.
  • For children aged 1-2 years, the usual dose is 0.5 mg/d.
  • For patients older than 2 years, the dose is 1 mg/d.
• Hydroxyurea, which increases fetal hemoglobin production, reduces the incidence of pain episodes and acute chest syndromes in some patients who are severely affected. The patient's hematologist determines the doses by performing frequent laboratory determinations.

Complications

• The patient with sickle cell disease is susceptible to a multitude of complications during this life-long disease. Patients may experience any or all entities at some time.
• Susceptibility to infection, mainly those due to encapsulated organisms secondary to splenic dysfunction, begins in infants aged 4-6 months. Overwhelming sepsis can occur at any time.
• Osteomyelitis, particularly that due to Salmonella and Staphylococcus species, occurs more commonly in patients with sickle cell disease than in the general population.
• Avascular necrosis of the femoral head occurs in 10% of patients, who may require hip arthroplasty.
• The severity of anemia may induce high output failure, cardiomegaly, and flow murmurs.
• Retinopathy, secondary to sequestration of blood in the conjunctival vessels, is marked by dilated and tortuous retinal vessels, microaneurysms, and retinal hemorrhage.
• Patients who sustain trauma to the eye resulting in hyphema are at risk for glaucoma due to physical obstruction of the trabecular meshwork by sickled blood inside the anterior chamber.
• Cholelithiasis, particularly in patients older than 6 years, can occur due to chronic hemolysis.
• Irreversible renal damage causing hyposthenuria is present in almost all patients by the age of 3 years and may progress to renal failure requiring transplantation.
• Hematuria due to sickling in the vas recta or renal papillary necrosis is common. Patients with refractory hematuria may require hospitalization for bedrest, hydration, and a trial of epsilon aminocaproic acid (2-8 g/d by mouth). Patients with the sickle cell trait later may develop hyposthenuria or hematuria.

Prognosis

• At any time, the patient with sickle cell disease can be faced with a myriad of potentially life-threatening and unpredictable complications.
• Most patients and families with a good understanding of the disease process have good outcomes due to compliance with medication regimes and an overall healthy attitude that promotes well-being.

Patient Education

• Patient's families should have genetic counseling and education regarding clinical manifestations associated with the disorder and its complications.
• Reinforcement should occur incrementally during the course of ongoing care.
• Families should be educated on the importance of hydration, diet, outpatient medications, and immunization protocol.
• Patients should be instructed on proper splenic palpation and observation of pallor, jaundice, and fever.
• Families should be encouraged to contact community sickle cell agencies for follow-up information, new drug protocols, and psychosocial support. Families should also follow the advances of gene therapy, bone marrow transplantation, and the usage of cord blood stem cells.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Sickle Cell Crisis.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

• AAP Committee on Genetics. Health supervision for children with sickle cell diseases and their families. American Academy of Pediatrics. Committee on Genetics. Pediatrics. Sep 1996;98(3 Pt 1):467-72. [Medline].
• Bachman D, Barkin R, Brennan S. Hematologic and oncologic disorders. In: Pediatric Emergency Medicine: Concepts and Clinical Practice. 2^nd ed. 1997:907-11.
• Berman B. Sickle cell anemia. In: Manual of Emergency Pediatrics. 4^th ed. 1992:61-4.
• Dampier C, Setty BN, Eggleston B, et al. Vaso-occlusion in children with sickle cell disease: clinical characteristics and biologic correlates. J Pediatr Hematol Oncol. Dec 2004;26(12):785-90. [Medline].
• Girot R, Begue P. [Sickle cell disease in childhood in 2004]. Bull Acad Natl Med. 2004;188(3):491-505; discussion 505-6. [Medline].
• Gulbis B, Haberman D, Dufour D, et al. Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events. The Belgian experience. Blood. Dec 16 2004;[Medline].
• Martin P, Pearson H. The hemoglobinopathies and thalassemias. In: Principles and Practice of Pediatrics. 2^nd ed. 1994:1660-1.
• Nordness ME, Lynn J, Zacharisen MC, et al. Asthma is a risk factor for acute chest syndrome and cerebral vascular accidents in children with sickle cell disease. Clin Mol Allergy. Jan 21 2005;3(1):2. [Medline].
• Serjeant GR, Serjeant BE, Thomas PW, et al. Human parvovirus infection in homozygous sickle cell disease. Lancet. May 15 1993;341(8855):1237-40. [Medline].
• Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease. Blood. Mar 1 1997;89(5):1787-92. [Medline].
• Wethers DL. Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment. Am Fam Physician. Sep 15 2000;62(6):1309-14. [Medline].

Article Last Updated: Nov 21, 2007