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Sickle Cell Treatment & Management

Author: Joseph E Maakaron, MD; Chief Editor: Emmanuel C Besa, MD more... (Used, Courtesy of Medscape)

Approach Considerations

The National Institutes of Health advises that optimal care for patients with sickle cell disease (SCD), including preventive care, is best achieved through treatment in clinics that specialize in the care of SCD. All patients with SCD should have a principal health care provider, who should either be a hematologist or be in frequent consultation with one. [39]

For sickle cell crisis, when the severity of the episode is assessable, self-treatment at home with bed rest, oral analgesia, and hydration is possible. Individuals with SCD often present to the emergency department (ED) after self-treatment fails. Do not underestimate the patient's pain. Failure to treat acute pain aggressively and promptly may lead to chronic pain syndrome. According to the 2003 BCHS acute painful crisis guidelines, these patients should receive analgesia within 30 minutes of entering the hospital, with the goal of achieving effective pain control by 60 minutes. [32]

If patients with SCD crisis are being transported by emergency medical services (EMS), they should receive supplemental oxygen and intravenous hydration en route to the hospital. Some areas have specialized facilities that offer emergency care of acute pain associated with SCD; many EDs have a standardized treatment plan in place.

Pain management should include four stages: assessment, treatment, reassessment, and adjustment. While considering the severity of pain and the patient's past response, follow consistent protocols to relieve the patient's pain.

The goals of treatment are symptom control and management of disease complications. Treatment strategies include the following seven goals:

  • Management of vaso-occlusive crisis

  • Management of chronic pain syndromes

  • Management of chronic hemolytic anemia

  • Prevention and treatment of infections

  • Management of the complications and the various organ damage syndromes associated with the disease

  • Prevention of stroke

  • Detection and treatment of pulmonary hypertension

Allogeneic bone marrow transplantation (BMT) can cure SCD, but it is difficult to decide which patients should be offered BMT. Many risks are associated with BMT, and the risk-to-benefit ratio must be assessed carefully. With the advent of cord blood stem cell transplantation and with the development of less immunoablative conditioning regimens, perhaps BMT will gain wider acceptance and use. The lack of availability of a matched donor may limit the utility of BMT.

An expert panel has released evidence-based guidelines for the treatment of SCD, including a strong recommendation that hydroxyurea and long-term, periodic blood transfusions should be used more often to treat patients. Other recommendations include the following [40, 41] :

  • Use of daily oral prophylactic penicillin up to age 5

  • Annual transcranial Doppler examinations between the ages of 2 and 16 years in patients with sickle cell anemia

  • Long-term transfusion therapy to prevent stroke in children with abnormal transcranial Doppler velocity (≥200 cm/s)

  • In patients with sickle cell anemia, preoperative transfusion therapy should be used to increase hemoglobin levels to 10 g/dL

  • Rapid initiation of opioids for the treatment of severe pain associated with a vasoocclusive crisis

  • Use of analgesics and physical therapy for the treatment of avascular necrosis

In July 2017, the US Food & Drug Administration (FDA) approved L-glutamine oral powder (Endari) for patients age 5 years and older to reduce severe complications of SCD. [70, 71]

Approval was based on data from a randomized, placebo-controlled trial in which, over the course of 48 weeks, patients receiving L-glutamine had fewer hospital visits for pain crises that resulted in treatment with parenteral narcotics or ketorolac (median three vs four), fewer hospitalizations for sickle cell pain (median two vs three), and fewer days in hospital (median 6.5 vs 11). In addition, fewer patients taking L-glutamine had episodes of acute chest syndrome (8.6% vs 23.1%). [70, 71]

Hydroxyurea Therapy

Although several pharmacological agents have been studied for the treatment of SCD, the only drug currently approved by the US Food and Drug Administration (FDA) for the treatment of SCD is hydroxyurea. For frequent and severe pain, long-term hydroxyurea is currently the accepted treatment. [42]

Hydroxyurea increases total and fetal hemoglobin in children with SCD. [43] The increase in fetal hemoglobin retards gelation and sickling of RBCs. Hydroxyurea also reduces levels of circulating leukocytes, which decreases the adherence of neutrophils to the vascular endothelium (see image below.) In turn, these effects reduce the incidence of pain episodes [43]and acute chest syndrome episodes. [39]

Effects of therapy with hydroxyurea.

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In 2008, a National Institutes of Health Consensus Development Conference concluded that “strong evidence supports the efficacy of hydroxyurea in adults to decrease severe painful episodes, hospitalizations, number of blood transfusions, and the acute chest syndrome. Although the evidence for efficacy of hydroxyurea treatment for children is not as strong, the emerging data are encouraging.” [39]

In a meta-analysis of the literature through 2007, Strouse et al studied the efficacy, effectiveness, and toxicity of hydroxyurea in children with SCD and found that fetal hemoglobin levels increased from 5-10% to 15-20%; hemoglobin concentration increased modestly (approximately 1 g/L) but significantly; hospitalizations decreased by 56-87%; and the frequency of pain crisis decreased. [44]

A phase III multicenter international clinical trial in 38 children with SCD found that hydroxyurea treatment can lower elevated cerebral blood flow velocities, which have been linked to stroke risk. After a mean of 10.1 months, transcranial Doppler (TCD) ultrasound showed that mean velocity had decreased 15.5 cm/sec in patients receiving hydroxyurea but had increased 10.2 cm/sec in those receiving observation only (P=0.02). Post hoc analysis according to treatment received showed that after 15 months, conversion from conditional to abnormal cerebral blood flow velocities occurred in 50% of patients in the observation group but none of those in the hydroxyurea group. [45]

In December 2017, the FDA approved Siklos (hydroxyurea) to reduce the frequency of painful crises and the need for blood transfusions in children 2 years of age and older and adolescents with sickle cell anemia who have recurrent moderate to severe painful crises. Siklos is the first hydroxyurea formulation to be FDA-approved for pediatric SCD. The approval was based on data from the ESCORT (European Sickle Cell Disease Cohort), an open-label single-arm trial that enrolled 405 pediatric patients with sickle cell disease from 2-18 years of age (274 children, ages 2-11 y; 108 adolescents, ages 12-16 y). The median change in fetal hemoglobin levels was 0.5 g/dL in 63 patients at 6 months and 0.7 g/dL in 83 patients at12 months after initiation of treatment. After 12 months of treatment, the drug exhibited an ability to increase fetal hemoglobin in all patients, and decrease the percentage of patients who experienced at least on vaso-occlusive episode, one episode of acute chest syndrome, one hospitalization due to SCD, or one blood transfusion. [72]

Hydroxyurea is usually prescribed by a hematologist, using rigorous selection criteria. Indications for hydroxyurea include the following:

  • Frequent painful episodes (six or more per year) [39]

  • History of acute chest syndrome

  • History of other severe vaso-occlusive events

  • Severe symptomatic anemia

  • Severe unremitting chronic pain that cannot be controlled with conservative measures

  • History of stroke or a high risk for stroke

Patients receiving hydroxyurea require frequent blood testing and monitoring, with special attention to development of leukopenia and/or thrombocytopenia. A good continuous doctor-patient relationship and rapport must exist to ensure that potential toxicity is identified at its onset.

Hydroxyurea is a potentially leukemogenic and carcinogenic agent. Children studied by a cooperative group remained on hydroxyurea for more than a year with only minor adverse effects, but potential complications from long-term use are not yet known.

For patients who fail to respond to hydroxyurea, repeated transfusions for a limited period may be an option. Management of constant pain is extremely difficult, and expert advice should be obtained.

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