INTRODUCTION

Section 2 of 10  

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

Background

Sickle cell anemia is a common reason patients of African descent seek emergency medical care. Although knowledge of the pathophysiological basis for sickle cell anemia has led to advances in its treatment, emergency physicians remain challenged by its varied clinical presentations, including vasoocclusive, hematologic, and infectious crises.

Pathophysiology

Sickle cell anemia is an autosomal recessive genetic disease that results from the substitution of valine for glutamic acid at position 6 of the beta-globin gene, leading to production of a defective form of hemoglobin, hemoglobin S (HbS).

Deoxygenation of the heme moiety of HbS leads to hydrophobic interactions between adjacent HbS molecules, which then aggregate into larger polymers, distorting the red blood cell (RBC) into the classic sickle shape.

The major consequence of this sickle shape is that RBCs become much less deformable; therefore, they obstruct the microcirculation. Tissue hypoxia, which promotes further sickling, results.

Sickle-shaped RBCs are rapidly hemolyzed and have a life span of only 10-20 days (vs the normal 120 d).

Patients who are homozygous for the HbS gene have full-blown sickle cell anemia. Patients who are heterozygous for the HbS gene are carriers of the condition. Under stressful conditions, carriers may display some clinical manifestations (eg, severe hypoxia). If both members of a couple are carriers, they have a 25% risk of producing a child who is homozygous for the HbS gene.

The clinical manifestations of sickle cell anemia are diverse, and any organ system may be affected. These manifestations commonly are divided into vasoocclusive, hematologic, and infectious crises.

Vasoocclusive crisis

A vasoocclusive crisis occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied. Pain is the most frequent complaint during these episodes, and it is ischemic in origin. Recurrent episodes may cause irreversible organ damage.

Bones (eg, femur, tibia, humerus, lower vertebrae) frequently are involved. Bone involvement causes pain. Involvement with the femoral head results in avascular necrosis.

Vasoocclusive crisis can involve the joints and soft tissue, and it may present as dactylitis or as hand and foot syndrome (painful and swollen hands and/or feet in children). When it involves abdominal organs, vasoocclusive crisis can mimic an acute abdomen. With repeated episodes, the spleen autoinfarcts, rendering it fibrotic and functionless in most adults with sickle cell anemia. The liver also may infarct and progress to failure with time. Papillary necrosis is a common renal manifestation of vasoocclusion, leading to isosthenuria (ie, inability to concentrate urine). Vasoocclusive crises can involve the lungs and cause an acute chest syndrome. The acute chest syndrome is difficult to diagnose in the ED setting. In one study, half of the patients who developed acute chest syndrome were admitted for a pain crisis.

Central nervous system manifestations of vasoocclusive crises are myriad, including cerebral infarction (children), hemorrhage (adults), seizures, transient ischemic attacks, cranial nerve palsies, meningitis, sensory deficits, and acute coma. Cerebrovascular accidents are not uncommon in children, and they tend to be recurrent. These patients are often maintained on hypertransfusion programs to suppress HbS.

Skin ulceration, especially over bony prominences (malleoli), and retinal hemorrhages are frequent complications of sickle cell vasoocclusive crises. Finally, vasoocclusion may involve the corpus cavernosum, preventing blood return from the penis and leading to priapism.

Hematologic crisis

Hematologic crises are manifested by a sudden exacerbation of anemia, with a corresponding drop in the hemoglobin level. This can be due to acute splenic sequestration in which sickled cells block splenic outflow, leading to the pooling of peripheral blood in the engorged spleen (seen in young patients with functioning spleens). Less commonly, it is due to hepatic sequestration.

Hematologic crises can also be caused by aplasia, in which the bone marrow stops producing new RBCs (aplastic crisis). This is most commonly seen in patients with parvovirus B19 infection or folic acid deficiency.

Infectious crisis

Infectious crises are due to underlying functional asplenia in most adults with sickle cell anemia, leading to defective immunity against encapsulated organisms (eg, Haemophilus influenzae, Streptococcus pneumoniae).

Individuals with infectious crisis also have lower serum immunoglobulin M (IgM) levels, impaired opsonization, and sluggish alternative complement pathway activation. Accordingly, persons with sickle cell anemia also exhibit increased susceptibility to other common infectious agents, including Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli.

Frequency

United States

Incidence of the homozygous state among black newborns is about 0.8%. Approximately 8% of blacks carry the mutated gene.

Mortality/Morbidity

Data from Quinn et al (2004) suggest improvement in mortality rates for patients with sickle cell disease over the past 30 years. Recent information suggests 85% survival to age 18 years. This study tracked 700 children for 18 years.

• Earlier data reported that among patients with sickle cell disease, approximately 50% do not survive beyond age 20 years, and most do not survive to age 50 years.

Race

The highest incidence is in those of African descent.

Sex

No sex predilection exists, since sickle cell anemia is not an X-linked disease.

CLINICAL

Section 3 of 10  

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

History

• Pain is the most common presentation of vasoocclusive crisis. Inquire about pain descriptors, including the following:
• • Location - Extremities, abdomen, back, flank, chest, and joints; whether monoarticular or oligoarticular
  • Duration and mode of onset (acuity of onset)
  • Character - Migrating, diffuse in the abdomen; pleuritic in acute chest syndrome
  • Previous similar episodes (painful crises tend to recur in the same pattern)
• Infection
• • Fever
  • Cough (whether productive, color of sputum)
  • Urinary symptoms (polyuria, hematuria, dysuria)
  • Shortness of breath or dyspnea (suggestive of acute chest syndrome)
• Neurological symptoms
  • Aphasia
  • Unilateral weakness
  • Paresthesias
• Visual blurring (retinal hemorrhage)
• Neck stiffness and severe headache (concerning for meningitis)
• Noticeable increase in weakness or pallor
• Syncope (most common presentation in acute sequestration crisis)
• Previous intake of analgesics (type and dose, if possible) and folic acid
• Surgical history (helps rule out other causes of abdominal pain)
• Previous hemoglobin levels and previous transfusions
• Vaccination
• • Pneumococcal vaccination
  • Influenza vaccination
  • Hepatitis B vaccination
• Precipitating event, preceding trauma, or family history of similar episodes

Physical

• Vital signs
• • Hypotension and tachycardia may be signs of septic shock or sequestration crisis. With the severe anemia that accompanies aplastic crisis, patients may exhibit signs of high-output congestive heart failure (CHF).
  • Orthostasis suggests hypovolemia.
  • Tachypnea suggests pneumonia, CHF, or acute chest syndrome. Hypoxia was commonly seen in patients with acute chest syndrome.
  • Fever suggests infection in children; however, it is less significant in adults unless it is a high-grade fever.
• Examine head and neck to look for meningeal signs or possible source of infection (eg, otitis, sinusitis).
• Auscultate the heart to search for signs of congestive heart failure.
• Auscultate the lungs to search for signs of pneumonia, CHF, or acute chest syndrome (similar to pulmonary embolism).
• Palpate for tenderness (abdomen, extremities, back, chest, femoral head) and hepatosplenomegaly.
• Observe for pallor, icterus, and erythema or edema of the extremities or joints.
• Perform neurological examination to search for focal neurological deficits.

Causes

• Vasoocclusive crises often are precipitated by the following:
• • Cold weather (due to vasospasm)
  • Hypoxia (flying in unpressurized aircraft)
  • Infection
  • Dehydration (especially from exertion or during warm weather)
  • Acidosis
  • Alcohol intoxication
  • Emotional stress
  • Pregnancy
  • Data also suggest a role for exertional stress, particularly when compounded with heat and hypovolemia.
• Aplastic crises often are preceded by the following:
• • Infection with parvovirus B19
  • Folic acid deficiency
• Ingestion of bone marrow toxins (eg, phenylbutazone)
• Acute chest syndrome has been linked to fat embolism and infections.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Aplastic crisis
Septic arthritis
Chronic splenomegaly
Pulmonary infarction
Rib infarction
Sepsis
Splenic sequestration
Synovial thrombosis
Upper respiratory tract infection

WORKUP

Section 5 of 10  

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

Lab Studies

• Assess hemoglobin and hematocrit levels. Anemia is often identified; however, a major drop in hemoglobin (ie, more than 2 g/dL) from previously recorded values indicates a hematological crisis. If the reticulocyte count is normal, splenic sequestration is the probable cause. If the reticulocyte count is low, an aplastic crisis is the probable cause.
• Obtain a leukocyte count. Leukocytosis is expected in all patients with sickle cell anemia. Major elevation in the WBC count (ie, >20,000 per mm³) with a left shift raises suspicion for infection.
• The platelet count is often elevated.
• In a peripheral smear, sickle-shaped RBCs are found along with target cells. Presence of Howell-Jolly bodies indicates that the patient is asplenic.
• Arterial blood gases (ABGs) may be ordered in patients who are in respiratory distress to supplement information provided by oxygen saturation monitoring. This will reflect the severity of pulmonary crisis. Serial ABGs are necessary to follow the response in pulmonary crisis.
• Order liver function tests in patients with abdominal pain. An elevated baseline indirect bilirubin level may be normal because of chronic hemolysis.
• Order an ECG for patients with symptoms of chest pain and/or pulse irregularities.
• Type and cross-match in case transfusion is necessary.
• Perform urinalysis if patient has fever or signs of urinary tract infection (UTI). Patients with sickle cell anemia often have hematuria and isosthenuria. If signs of urinary tract infection are present, obtain a urine Gram stain and culture.
• If the diagnosis of sickle cell anemia is uncertain, a sickling test will establish the presence of HbS gene. It will not, however, differentiate between individuals who are homozygous and those who are heterozygous.
• Hemoglobin electrophoresis, though not immediately useful in the ED, differentiates individuals who are homozygous from those who are heterozygous.
• • A homozygous patient will have hemoglobin SS (HbSS, 80-90%), hemoglobin F (HbF, 2-20%), and hemoglobin A2 (HbA2, 2-4%).
  • A carrier patient will have HbSS (35-40%) and hemoglobin A (HbA, 60-65%).
  • The test is not accurate in a patient who has recently received blood transfusions.

Imaging Studies

• Chest radiography
• • Perform in patients with respiratory symptoms.
  • Radiographic findings may initially be normal in patients with acute chest syndrome.
• Bone radiography
• • Perform in patients with localized bone tenderness.
  • Do not differentiate between osteomyelitis and bone infarction in the early stages. Radiographic signs of osteomyelitis may not appear for 8-10 days.
  • A view of the vertebral column shows typical fish-mouth appearance of vertebrae in patients with sickle cell anemia. This is due to expansion of the bone marrow.
• Ultrasonography
• • Use in patients with abdominal pain to rule out cholecystitis or an ectopic pregnancy.
  • Assess liver and spleen size.
• Head CT or MRI is used in cases of neurologic crisis.
• Bone scans can aid in early differentiation of bone infarction and osteomyelitis.

TREATMENT

Section 6 of 10  

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

Prehospital Care

• When severity of patient's crisis is assessable, self-treatment at home with bed rest, oral analgesia, and hydration is possible.
• Individuals with sickle cell anemia often present to the ED after failing self-treatment. Do not underestimate the patient's pain.
• If patients with sickle cell anemia are in crisis and are being transported by EMS, they should receive supplemental oxygen and intravenous hydration en route to the hospital.

Emergency Department Care

Hydration and analgesia are the mainstays of treatment in the ED. Narcotic analgesia is most frequently used in the ED.

Some very preliminary data suggest a possible benefit of nalbuphine hydrochloride (Nubain) compared with morphine sulphate (Buchanan, 2005).

• Administer oral hydration if the patient is having a mild episode, is not vomiting, and can tolerate oral fluids.
• Administer IV fluids (at least 3-4 L normal saline solution [NSS]). Ensure accurate intake-output measurements by inserting a Foley catheter or carefully recording amounts. Take care not to overload the patient.
• While considering the severity of pain and the patient's past response, follow consistent protocols to relieve the patient's pain.
• Oxygen supplementation is only beneficial if patient has hypoxia. Intubation and mechanical ventilation may be required in patients in whom cerebrovascular accidents have occurred and in patients with acute chest syndrome.
• Simple blood transfusion is indicated in patients in aplastic crisis and acute sequestration crisis.
• • Exchange blood transfusions are indicated in cases of cerebrovascular accidents and acute chest syndrome. They are performed occasionally in patients with acute sequestration crisis or in cases of priapism that do not resolve after adequate hydration and analgesia (see Priapism). Exchange transfusion consists of replacing the patient's RBCs by normal donor RBCs, decreasing HbS to less than 30%.

Consultations

• Hematologic consultation may be necessary.
• If retinopathy or hyphema is suspected and visual symptoms are present, an ophthalmology consultation is warranted.
• In case of priapism that does not resolve after 6 hours of hydration and analgesia, consult a urologist for aspiration of corpus cavernosum or shunting.
• If avascular necrosis of the hip is suspected in a patient with hip pain and difficulty in walking, consult an orthopedist for possible hip joint replacement. Consult an orthopedist if osteomyelitis is suspected.

MEDICATION

Section 7 of 10  

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

Medications involved in treatment of sickle cell anemia include analgesics for pain and antibiotics for infections.

Drug Category: Analgesics

Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties.

Drug Category: Antibiotics

These agents are used for treatment of suspected or confirmed infections.

Drug Category: Antiemetics

These agents are useful in the treatment of symptomatic nausea.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Indications for hospital admission are as follows:
• • Pulmonary, neurological, or infectious crisis
  • Vasoocclusive pain that does not resolve after 4-6 hours and 2 doses of narcotics in the ED
  • Inability to maintain adequate hydration if discharged home
  • Uncertain diagnosis

Further Outpatient Care

• If improvement is shown after 6 hours in the ED, patient may be discharged home with strict instructions to ingest large amounts of fluids and to return if pain recurs, temperature increases, or new symptoms develop.
• Arrange follow-up in a hematology clinic so that appropriate counseling can be given and new drugs, such as hydroxyurea, can be tried. Such drugs are believed to decrease the frequency of sickling crisis by increasing the percentage of fetal hemoglobin (HbF) in blood.

In/Out Patient Meds

• Folic acid should be prescribed to those who are not already taking it.
• Discharge patient on oral analgesics for a week. Up to 2 doses of narcotics can be administered in ED over a period of 4-6 hours.
• Oral drugs for mild pain include acetaminophen, ibuprofen, aspirin, and codeine. If pain is moderate, oxycodone or methadone can be administered.
• Administer parenteral drugs for severe pain. Morphine is the drug of choice, but meperidine with promethazine can be used.
• Antibiotics are indicated when an infection is suspected, when body temperature is higher than 38 degrees Celsius, or when a patient has localized bone tenderness. Fever in children is strongly suggestive of infection. It has been found that signs of infection are more accurate in children than in adults.
• Common infections include pneumonia, bronchitis, pyelonephritis, cystitis, osteomyelitis, meningitis, and sepsis. Recommended parenteral antibiotics include cephalosporins (eg, ceftriaxone, cefuroxime).
• If the patient is discharged home, oral antibiotics (eg, Augmentin, Ceclor) are useful. If the patient has localized bone tenderness, seek antibiotic coverage for S typhimurium and S aureus.

Transfer

• Transfer is only applicable if exchange transfusion or ICU is not available.

Deterrence/Prevention

• Measures to prevent sickle cell crisis include the following:
• • Adherence to an immunization schedule
  • Pneumococcal vaccine
  • Hepatitis vaccine
  • Foot care and protective shoes
  • Periodic health care visits
  • Biannual medical visit for those older than 30 years

Complications

• Sickle pulmonary disease is due to a chronic hypoxic state, recurrent infarctions, and infections. It is a form of chronic obstructive pulmonary disease (COPD), and it usually develops in patients older than 30 years. Cor pulmonale may ensue, and the management is that of patients with right-sided heart failure and COPD.
• Cholelithiasis may occur because gallstones form as a result of chronic hemolytic anemia. Ultrasound is diagnostic. If symptomatic, cholecystectomy is indicated.
• Ophthalmologic complications include retinopathy, which can be proliferative and nonproliferative, as well as retinal infarcts and retinal detachment. Findings on ophthalmoscopic exam include corkscrew vessels in the conjunctiva and salmon patches on the retina.
• Transfusion-related illnesses that are due to multiple transfusions consist of alloimmunization, hepatitis, and HIV exposure. The risk of hemosiderosis is also present.
• Leg ulcers may result from venous stasis and chronic hypoxia. These may become infected. Management is the same as with other stasis ulcers.
• Avascular osteonecrosis may result from chronic hypoxia in weight-bearing joints, commonly the femoral head. Joint replacement is often necessary.
• Psychological problems
• • Patients may experience depression, anxiety, and chronic pain behavior.
  • Counseling is crucial. Ensure an appropriate physician-patient relationship.
  • Anxiolytics and amitriptyline may be used.

Prognosis

• Most patients with sickle cell anemia suffer from bacterial infections, painful crisis, and fatigue secondary to chronic anemia.
• Half of patients with sickle cell anemia die when younger than 20 years. Most do not survive to the age of 50 years.

Patient Education

• Teach patients to seek medical care in certain situations, including the following:
• • Persistent fever (>38.3°C)
  • Chest pain, shortness of breath, nausea, and vomiting
  • Abdominal pain with nausea and vomiting
  • Persistent headache not experienced previously
• Patients should avoid the following:
• • Alcohol
  • Nonprescribed prescription drugs
  • Cigarettes, marijuana, and cocaine
  • Seeking help in multiple institutions
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Anemia and Sickle Cell Crisis.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Carriers may show evidence of hemoglobinopathy under severe stress and hypoxic states.
• Carriers may have hematuria, leg ulcers, splenic infarcts, and hyphema.
• Sickle beta-thalassemia and sickle cell disease
• • Each patient varies in severity and variety of clinical manifestations.
  • Patients with either of these disorders can have splenomegaly and delayed autoinfarction of the spleen.
  • Patients with sickle beta-thalassemia tend to have more vasoocclusive symptoms than do patients with sickle cell anemia.
  • Patients with sickle cell disease tend to have more proliferative retinopathy, renal disease, acute chest syndrome, and avascular osteonecrosis than do patients with sickle beta-thalassemia.

Special Concerns

• Sickle cell disease and pregnancy
• • Patients who are pregnant and have sickle cell disease are at increased risk for crisis, toxemia, pyelonephritis, thrombophlebitis, and spontaneous abortion compared to the general population.
  • Prophylactic transfusion with special concern for folic acid replacement has been shown to decrease the incidence of vasoocclusive crisis during pregnancy.
  • In the past, pregnancy was strongly discouraged, and tubal ligation often was performed.

REFERENCES

Section 10 of 10

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

• Bergeron MF, Cannon JG, Hall EL. Erythrocyte sickling during exercise and thermal stress. Clin J Sport Med. Nov 2004;14(6):354-6. [Medline].
• 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. Oct 15 2005;45(5):716-24. [Medline].
• Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. Sep 11 1997;337(11):762-9. [Medline].
• Eberst M. Hereditary hemolytic anemias. In: Tintinalli JE, Ruiz E, Krome RL, eds. Emergency medicine: A Comprehensive Study Guide. 4th ed. New York: McGraw-Hill;1996:987-990.
• Okpala I. The management of crisis in sickle cell disease. Eur J Haematol. Jan 1998;60(1):1-6. [Medline].
• Pollack CV. Emergencies in sickle cell disease. Emerg Med Clin North Am. May 1993;11(2):365-78. [Medline].
• Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. Jun 1 2004;103(11):4023-7. [Medline].
• Sears DA. The morbidity of sickle cell trait: a review of the literature. Am J Med. Jun 1978;64(6):1021-36. [Medline].
• Steen RG, Emudianughe T, Hankins GM, et al. Brain imaging findings in pediatric patients with sickle cell disease. Radiology. Jul 2003;228(1):216-25. [Medline].
• Stephens CR. Sickle cell disease: a review of state-of-the-art emergency management and outcome-effective therapy. Emerg Med Rep. 1999;20:183-192.
• Vichinsky E. Sickle cell disease. In: Schwarz GR, Cayton CG, et al, eds. Principles and Practice of Emergency Medicine. 3rd ed. Vol 2. Philadelphia: Lea & Febiger;1992:2019-2024.
• Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. Jun 22 2000;342(25):1855-65. [Medline].
• Wirthwein DP, Spotswood SD, Barnard JJ. Death due to microvascular occlusion in sickle-cell trait following physical exertion. J Forensic Sci. Mar 2001;46(2):399-401. [Medline].
• Zurcher R. Sickle cell anemia. In: Hamilton GC, ed. Presenting signs and symptoms in the emergency department. Philadelphia: Lippincott Williams & Wilkins;1993:328-336.

Article Last Updated: Jan 11, 2007