Sickle Cell Anemia Treatment & Management

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.^[38]

When severity of the patient's crisis 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, analgesia should be administered with 30 minutes of entering the hospital, with the goal of achieving effective pain control by 60 minutes.^[29]

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. The 2003 BCHS guidelines recommend a 50/50 nitrous oxide/oxygen mix for pain control in the ambulance, limited to no more than 60 minutes.^[29] 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 4 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 7 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.

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.

Hydroxyurea increases total and fetal hemoglobin in children with sickle cell disease.^[39] 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^[39] and acute chest syndrome episodes.^[38]

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.”^[38]

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.^[40]

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

• Frequent painful episodes (6 or more per year)^[38]
• 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.

Transfusions are not needed for the usual anemia or episodes of pain associated with SCD. Urgent replacement of blood is often required for sudden, severe anemia due to acute splenic sequestration, parvovirus B19 infection, or hyperhemolytic crises. Transfusion is helpful in acute chest syndrome, perioperatively, and during pregnancy. Acute red cell exchange transfusion is indicated in the following situations:

• Acute infarctive stroke
• Severe acute chest syndrome
• Multiorgan failure syndromes
• Right upper quadrant syndrome
• Priapism that does not resolve after adequate hydration and analgesia

Transfusion-related complications include alloimmunization, infection, and iron overload. Treatment of iron overload is becoming easier with the new oral chelators.

Alloimmunization is a common problem that arises from the differences in certain minor red cell antigens found in the predominantly black patient population and the mostly white blood donors. Matching for C, E, Kell, JKB (Kidd), and Fya (Duffy) antigens can significantly reduce alloimmunization.

Transfusion and surgery

Intraoperative and postoperative complications may result from hypoxia, dehydration, or hypothermia that occurs during or after a surgical procedure. More complex procedures or longer duration of anesthesia times are more likely to lead to acute chest syndrome or other complications. Providing preoperative transfusion may decrease the risk.

Although one study demonstrated no overall difference in the complication rate among subjects who received either preoperative exchange or simple transfusion, it provided little guidance for what type of transfusion would be best in individual situations.

In general, raising the hemoglobin concentration to between 10 g/dL and 12 g/dL provides the patient with approximately 20-30% hemoglobin A. The presence of this fraction of normal hemoglobin may provide some protection from complications. Many anesthesiologists require a hemoglobin concentration of more than 10 g/dL prior to the procedure.^[41]

When the patient’ baseline hemoglobin level is above 10 g/dL, the approach is less certain. If the complexity of the surgical procedure or the duration and risk of anesthesia is considerable, exchange transfusion or erythrocytapheresis can reduce the hemoglobin S concentration to 30%, while keeping the total hemoglobin level below 12 g/dL.

In patients undergoing retinal surgery, the HbS concentration or combined concentration of HbS and HbC needs to be reduced to less than 30% (increase the hemoglobin A concentration to 70%).

Individualize all other situations based on the complexity of the procedure and underlying medical condition.

Treatment of iron overload

With continued transfusion, iron overload inevitably develops and can result in heart and liver failure and multiple other complications. Serum ferritin is an inaccurate means of estimating the iron burden; liver iron evaluation, or perhaps MRI, is a more accurate means of determining tissue iron concentration and the response to chelation.

Three agents are available for iron chelation: desferrioxamine, deferasirox, and deferiprone (orphan drug in the United States).

Desferrioxamine is an efficient chelator. However, it needs to be given parenterally or subcutaneously by prolonged infusion and nearly every day (5 days a week), which has limited its effectiveness in many patients.^[42]

Deferasirox has a capacity similar to desferrioxamine in chelating iron, but it is administered orally. Renal toxicity might be a limiting factor in its use, but it is generally safe.

Deferiprone does not seem to be as effective as the other 2 agents but can be taken orally and selectively removes cardiac iron. It might be most effective when used with desferrioxamine or deferasirox. It is used as a second-line therapy.

A novel new iron chelator is being developed but is still in the clinical testing phase.^[43]

Erythrocytapheresis

Erythrocytapheresis is an automated red cell exchange procedure that removes blood that contains HbS from the patient while simultaneously replacing that same volume with packed red cells free of HbS.^[44] Transfusion usually consists of sickle-negative, leuco-reduced, and phenotypically matched blood for red cell antigens C, E, K, Fy, and Jkb.

The procedure is performed on a blood cell processor (pheresis machine) with a continuous-flow system that maintains an isovolemic condition. RBCs are removed and simultaneously replaced, with normal saline followed by transfused packed RBCs along with the patient's plasma. The net RBC mass/kg is calculated for each procedure based on the measured hematocrit of the transfused and removed blood and the total RBC volume transfused.

Erythrocytapheresis thus has the advantage of controlling iron accumulation in patients with SCD who undergo long-term transfusion, as well as the ability to achieve adequate Hb and HbS concentrations without exceeding the normal concentration. This precision is achieved because, before the start of the transfusion, the computer in the pheresis machine calculates the expected amount of packed RBCs required to obtain a specific posttransfusion hemoglobin level, using various physiologic parameters (eg, height, weight, Hb level). Further, erythrocytapheresis requires less time than simple transfusion of similar blood volumes.

Although erythrocytapheresis itself is more expensive than simple transfusion, the additional costs associated with simple transfusions (ie, those of chelation and organ damage due to iron overload) make erythrocytapheresis more cost-effective than simple transfusion programs. Central venous access devices can safely be used for long-term erythrocytapheresis in patients with SCD with a low rate of complications.

See Ophthalmic Manifestations of Sickle Cell Anemia for more information on this topic.

Vaso-occlusive crisis is treated with vigorous intravenous hydration and analgesics. Intravenous fluids should be of sufficient quantity to correct dehydration and to replace continuing loss, both insensible and due to fever. Normal saline and 5% dextrose in saline may be used. Treatment must be in an inpatient setting.

A retrospective chart review from a tertiary center identified characteristics associated with admission and longer length of stay in patients who presented to the ED in vaso-occlusive crisis.^[45] Predictors of admission included the following:

• Higher pain score at triage
• Older age
• Increased systolic blood pressure

Factors associated with longer length of hospital stay included the following:

• Higher pain score at triage
• Older age
• Increased polymorphonuclear count
• Homozygous SCD type

The authors conclude that these characteristics will help healthcare providers predict and plan admission and management of children with SCD.

The randomized BABY HUG study has demonstrated that hydroxyurea (hydroxycarbamide) significantly reduces the incidence of vaso-occlusive crisis and dactylitis in very young children.^[46] The primary toxicity observed was neutropenia. Further study is needed to evaluate long-term treatment effects on growth and development as well as renal, lung, and CNS function. A randomized, placebo-controlled trial in adults did not demonstrate a significant improvement in the time to resolution of vaso-occlusive crisis.^[47]

Pain control is best achieved with opioids. Morphine is the drug of choice.

According to the 2003 BCSH acute painful crisis guidelines, management of severe pain should involve the use of paracetamol (acetaminophen) and NSAIDs in conjunction with opioids. Laxatives should be prescribed when opioids are used. Pethidine (meperidine) is contraindicated for routine analgesia.^[29]

Morphine dosing has to be individualized. The drug should be given intravenously, hourly at first. Once the effective dose is established, it should be administered every 3 hours. After 24-48 hours, as pain is controlled, equivalent doses of sustained-release oral morphine should be given.

The 2003 BCSH guidelines state that patient-controlled analgesia may be helpful, provided that sufficient expertise and appropriate protocols are available. Most of the drug should be given in boluses, with a low rate of infusion. The guidelines also recommend oral analgesia as preferential in treating SCD pain in children, although very severe pain may be best managed with parenteral analgesia.^[29]

When marked improvement occurs, the patient may be discharged home on sustained-release oral morphine, and the dose is reduced gradually over several days. Morphine elixir can be used to control breakthrough pain.

Treatment of acute chest syndrome consists of oxygen, antibiotics, incentive spirometry, simple transfusion, and bronchodilators. The 2003 BCSH guidelines strongly advocate the use of incentive spirometry for patients with chest or back pain.^[29] The aim is to reduce the concentration of HbS to less than 30%. If the hematocrit is 30% or higher, an exchange transfusion must be performed. This can be done by removing 1 unit of blood, transfusing 1 unit, and repeating the process or by using a continuous-flow pheresis machine.

Adults, in general, need a higher rate of transfusions and longer hospitalization than children. Overhydration must be avoided.

Treatment measures include oxygen therapy with close monitoring for hypoxemia with continuous pulse oximetry or frequent assessment of blood gases, empiric treatment with intravenous antibiotics active against S pneumoniae after appropriate cultures are obtained, and empiric addition of a macrolide antibiotic because chlamydial and mycoplasmal infections are common. Antibiotic changes are based on response to therapy and results of cultures and sensitivities.

Simple transfusion administered early may halt progressive respiratory deterioration, preventing complications such as increasing tachypnea and need for supplemental oxygen. Transfused red cells should be matched for C, D, E, and Kell antigens to minimize the risk of alloimmunization.

Analgesics are required. Agents that do not suppress respiration, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), can be used. Narcotic agents may be used judiciously for more severe pain. Other supportive measures include careful hydration that avoids volume overload, which may contribute to pulmonary infiltrates and exacerbate hypoxia.

The role of corticosteroids in nonasthmatic patients with acute chest syndrome remains a topic of clinical research. Elevated levels of serum phospholipase A2 levels have been found to be associated with acute chest syndrome and might predict its occurrence. In pilot studies, transfusion of patients who had pain, no obvious acute chest syndrome, and increased serum phospholipase A2 levels have thwarted its development.

For episodes of severe hypoxia, rapid progression, diffuse pulmonary involvement, and failure to improve, erythrocytapheresis is indicated. Intensive care is indicated for patients in severe hypoxia or respiratory distress, as respiratory decompensation can rapidly require mechanical ventilation.

Obtain appropriate cultures, but treat expectantly for Streptococcus pneumoniae and Mycoplasma pneumoniae. Administer oxygen if saturation is less than 94%. If that level cannot be maintained at a fraction of inspired oxygen (FiO₂) of 0.4, provide simple transfusion (avoid raising hematocrit to more than 36%). If no improvement is seen, reduce the HbS level to 30% with erythrocytapheresis or exchange transfusion. The process can rapidly progress to respiratory failure. Ventilatory assistance may be required.

Some patients have repeated severe acute chest syndrome. Chronic transfusion reduces the recurrence and hydroxyurea reduces the rate of acute chest syndrome by about half.

Chronic pain is managed with long-acting oral morphine preparations and acetaminophen and NSAIDs. NSAIDs are particularly effective in reducing deep bone pain.

Many patients may require breakthrough oral opiates as well. The weak agents, codeine and hydrocodone, are used first. Sustained-release long-acting oral morphine is reserved for more severe cases. Hydromorphone may be used but is considerably more expensive. Meperidine should be avoided.

The addition of tricyclic antidepressants may reduce the dose and need for opiates by interfering with pain perception. In addition, many patients with chronic pain are depressed, and lifting the depression has a salutary effect on the pain as it elevates the pain threshold.

Hydroxyurea may decrease the frequency and severity of pain episodes.^[39] The safety of long-term hydroxyurea use in children remains uncertain, however (see Hydroxyurea Therapy, above).

Nonpharmacological approaches to pain management may have a substantial impact. These include physical therapy, heat and cold application, acupuncture and acupressure, hypnosis, and transcutaneous electric nerve stimulation (TENS). Support groups are also useful.

Inform parents and children that recurring pain is expected. Assist them in developing an approach that allows continued normal activities even with pain. Instruct parents and family members to provide sympathy but to do so with encouragement and support, so as to help the child accept the pain, rather than to submit to it.

Parents and family members are encouraged to provide local measures and over-the-counter drugs for mild pain. Physicians suggest keeping on hand a small supply of a mild narcotic analgesic for pain that does not respond to lesser measures.

Pain that does not respond to the above measures almost always requires hospitalization. In such cases, treat with morphine or other major narcotic analgesics in doses sufficient to provide a reasonable degree of relief. Continuous infused morphine is most effective. Attempting to resolve pain by providing 1-2 doses of parenteral narcotics in the emergency department is inadvisable, since moderately severe sickle cell pain is expected to persist for several days.

Choose a dosage to provide reasonable pain relief with precautions to avoid oversedation and respiratory depression. A starting dose of morphine (0.05-0.01 mg/kg/h) is suggested following a bolus dose to provide a reasonable degree of pain relief. Adjust according to patient response. Patient-controlled analgesia with self-administered bolus morphine and low-dose continuous intravenous infusion is effective and well accepted by patients.

Fentanyl and nalbuphine have also been used as continuous IV infusion. Ketorolac can be given along with opioid analgesics and typically reduces the opioid dose required to achieve the desired effect.

Opioid dependence seldom occurs because the duration of sickle pain is brief (5-7 d). Addiction, described as narcotic-seeking behavior, is rarely encountered. It can result if a patient uses narcotics for euphoriant or stimulant effects rather than analgesia. Narcotic addiction in people with SCD is no more common than in the general population and may be minimized with a carefully designed analgesic regimen.

When drug addiction with substance abuse is present, however, difficult management problems ensue. These require a team approach involving counselors, substance abuse specialists, hematologists, and pain management experts.

Anemia is usually well tolerated. Because of the high RBC turnover, folate stores are often depleted. No scientific evidence shows that patients develop folate deficiency; however, folic acid (1 mg/d) is commonly prescribed for adults to prevent development of megaloblastic anemia due to increased folate requirements caused by hemolysis. Folic acid supplementation may raise the Hb level and support a healthy reticulocyte response.

The primary physician should initiate folic acid therapy, as follows:

• For patients younger than 6 months, the usual dose is 0.1 mg per day
• For infants aged 6 months to 1 year, 0.25 mg per day
• For children aged 1-2 years, 0.5 mg per day
• For patients older than 2 years, 1 mg per day

Women who are menstruating should be checked for coexisting iron deficiency and, if it is found, given iron supplements. An adequate overall diet is essential.

Blood transfusion is indicated only in specific situations. These include acute chest syndrome, stroke, abnormal findings on transcranial Doppler in children (for stroke prevention), pregnancy, and general anesthesia. The aim is to decrease the concentration of HbS to 30% or less. Transfusion may also be required during aplastic crisis.

For anemic crisis with splenic sequestration, give early red cell transfusions because the process can rapidly progress to shock. Do not allow hemoglobin (Hb) levels to rise to more than 10 g/dL, since the spleen may disgorge trapped cells, which can create a relative polycythemia and increased blood viscosity.

Children who experience a single sequestration event frequently have recurrences. Surgical splenectomy or a short-term transfusion regimen has been suggested for this complication.

Transfusion is required in an aplastic crisis if the anemia is symptomatic (eg, dyspnea, signs of hypovolemia). Because aplastic crises are self-limited, transfusion may be avoided if the child is stable and can be adequately observed. If hospitalization is required, use precautions to prevent transmission of parvoviral infection to patients who are immunosuppressed or caretakers who are pregnant.

Neonatal screening, penicillin prophylaxis, appropriate immunizations (particularly against Streptococcus pneumoniae), and parental teaching have remarkably minimized infection-related morbidity and mortality. Prevention of infection also improves chances of survival in SCD. In the adult patient, all infections must be treated promptly with broad-spectrum antibiotics. Once a causative organism is identified, therapy is tailored according to its antibiotic sensitivity.

Antibiotics are indicated when an infection is suspected, when body temperature is higher than 38° C, or when a patient has localized bone tenderness. The 2003 BCSH guidelines also recommend the use of broad-spectrum antibiotics in the patient who is systemically ill or has chest involvement.^[29] Fever in children is strongly suggestive of infection. Signs of infection have proved to be more accurate in children than in adults.

Recommended parenteral antibiotics include cephalosporins (eg, ceftriaxone, cefuroxime) and macrolides for acute chest syndrome. If the patient is discharged home, oral antibiotics (eg, amoxicillin-clavulanic acid, clarithromycin, cefixime) are useful in selected cases. If the patient has localized bone tenderness, the antibiotic selected should provide coverage for S typhimurium and S aureus.

Penicillin prophylaxis significantly reduces the incidence of infection with encapsulated organisms—in particular, S pneumoniae —and may decrease the mortality rate. Begin at age 2 months with 125 mg bid of penicillin V or G; at 3 years, increase the dose to 250 mg bid. Prophylaxis should continue until age 5 years or the early teens. Recent trials have shown that the susceptibility for septicemia with encapsulated organisms persists well into adulthood, and the benefit of continuing penicillin prophylaxis is now the subject of clinical research. If the patient is allergic to penicillin, erythromycin may be substituted.

As with all long-term medication regimens, maintaining compliance can be difficult. Therefore, remind parents of the importance of prophylaxis at each visit.

Protein-conjugated pneumococcal vaccines (PCVs) that effectively protect children against invasive infections are now extensively used. The 7-serotype PCV (PCV7) in combination with penicillin prophylaxis and PPV23 booster vaccination offers the best hope for improved prevention against S pneumoniae infection. The vaccine is given at age 2 years, with a booster dose at age 5 years.

In one study, more than two thirds of S pneumoniae isolates stereotyped were PCV7 serotypes and included most penicillin-nonsusceptible strains. Most nonvaccine-serotype isolates were penicillin-sensitive.

In addition to receiving pneumococcal vaccination, pediatric patients with SCD should follow the immunization schedule currently recommended by the American Academy of Pediatrics, including meningococcal vaccination. Meningococcal prophylaxis is administered as a single quadrivalent vaccine when the child is older than 2 years.

Treatment of acute cholecystitis in patients with sickle cell disease does not differ from that for the general population. Patients receive antibiotics and general supportive care and may consider elective cholecystectomy several weeks after the acute episode subsides. Elective laparoscopic cholecystectomy in a well-prepared patient has become the standard approach for symptomatic disease. If patients present with right upper quadrant abdominal pain, evaluate the gallbladder with ultrasonography. Provide appropriate medical and supportive care for cholecystitis if stones are visualized, if gallbladder walls are thickening, or upon signs of ductal inflammation.

At the onset of priapism, patients should be advised to drink extra fluids, use oral analgesics, and attempt to urinate. A nightly dose of pseudoephedrine (30 mg orally) may prevent priapism in some cases.

For episodes that last more than 2 hours, patients should go to the emergency department to receive intravenous hydration and parenteral analgesia. According to one protocol, if detumescence does not occur within 1 hour after arrival in the emergency department, penile aspiration followed by irrigation of the corpora with a 1:1,000,000 solution of epinephrine in saline is initiated.^[48] (The procedure should be performed within 4-6 h of priapism onset.)

The concomitant use of automated red cell exchange transfusions to reduce the HbS level to less than 30% may also be considered, especially if early intervention with irrigation fails. Should the condition recur despite aspiration and local instillation of vasoactive drugs, consider shunting. In this procedure, known as the Winter procedure, a shunt is created between the glans penis and the distal corpora cavernosa; this allows blood from the distended corpora cavernosa to drain into the uninvolved corpus spongiosa. A larger shunt may be created if this is not successful.

Complications of priapism and treatment include bleeding from the holes placed in the penis as part of the aspiration or shunting procedures, infections, skin necrosis, damage or strictures of the urethra, fistulas, and impotence. If impotence persists for 12 months, the patient may wish to consider implantation of a semirigid penile prosthesis.

New approaches to prevent recurrent priapism include use of phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil). In pilot studies, long-term treatment with these agents alleviated recurrent priapism in some patients with SCD.^[49]

Leg ulcers are treated with debridement and antibiotics. Zinc oxide occlusive dressing (Unna boot) and leg elevation are employed. Transfusion may accelerate healing. Skin grafting may be necessary in recalcitrant cases. Leg ulcers may result from venous stasis and chronic hypoxia and may become infected. Management is the same as with other stasis ulcers.

Adults with SCD should be evaluated for known stroke risk factors and managed according to the 2011 AHA/ASA primary stroke prevention guidelines.^[32]

The AHA and ASA also provided guidelines in 2011 for the prevention of stroke in patients with stroke or transient ischemic attack. These secondary stroke prevention guidelines include recommendations for controlling risk factors and the use of antiplatelet agents. Other therapies to consider in preventing recurrent cerebral ischemic attacks in adults with SCD include regular blood transfusions (to reduce HbS to < 30%-50% total hemoglobin), hydroxyurea, or bypass surgery for advanced occlusive disease.^[50]

Transfusion therapy, aimed at keeping the proportion of HbS below 30%, is now considered standard care for primary and secondary stroke prevention in children with SCD. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) showed that regular blood transfusions produced a marked (90%) reduction in first stroke in asymptomatic high-risk children who had 2 abnormal transcranial Doppler (TCD) studies with velocities of 200 cm/s or greater.^[51] According to the 2011 AHA/ASA primary stroke prevention guidelines, this form of therapy has been proven effective for reducing stroke risk in those children at increased risk for stroke.^[32]

During the transfusion period, most of the TCD studies reverted to or toward normal. Once the transfusion program was stopped, however, there was an unacceptably high rate of TCD reversion to high risk, as well as to actual strokes.^[37]

Unless long-term transfusion therapy is provided, 70-90% of children who experience a single stroke have subsequent events. As patients grow into adulthood, the transfusion frequency may be decreased, but whether it can be discontinued remains unclear. Many believe that lifelong transfusion therapy is necessary to completely eliminate recurrences in patients with SCD. The AHA/ASA 2011 primary stroke prevention guidelines endorse (pending further study) the continued use of transfusion, even in those with TCD velocities that return to normal.^[32] Iron overload from repeated transfusions requires chelation therapy after 2-3 years.

Erythrocytapheresis is now increasingly used as an alternative to simple transfusion. This procedure allows rapid reduction of HbS concentrations to less than 30% without significantly increasing total hemoglobin concentration post transfusion (see Transfusion, above).

For children with a human leukocyte antigen (HLA)–matched sibling, a consortium has demonstrated that the risk of recurrent stroke can be greatly reduced with allogeneic bone marrow transplantation. This offers an alternative to long-term transfusion and iron chelation.

According to the AHA/ASA primary prevention guidelines, hydoxyurea or bone marrow transplantation might be an option for children at high risk for stroke in whom RBC transfusion is contraindicated.^[32]

Pulmonary hypertension, defined as a tricuspid regurgitant jet velocity (TRJV) greater than 2.5 m/s on echocardiography, is an emergent complication seen in 32% of adult patients with SCD and is associated with a high mortality rate. Pulmonary hypertension is a complication of chronic intravascular hemolysis. Additional factors contributing to pulmonary hypertension include older age, renal insufficiency, cardiovascular disease, cholestatic hepatopathy, systolic hypertension, high hemolytic markers, iron overload, and a history of priapism.

Even modestly increased pulmonary artery pressures are associated with severe reduction in exercise capacity, as assessed by both the 6-minute walk and cardiopulmonary exercise testing, and herald a poor prognosis. Both pulmonary hypertension and cardiac sequelae, such as diastolic dysfunction, have been associated with accelerated mortality in the sickle cell disease population.

For symptomatic patients, hydroxyurea and chronic transfusion have been used. Enothelin-1 receptor antagonists (eg, bosentan) and phosphodiesterase inhibitors (eg, sildenafil) have been used, but their role is limited by other complications. Cor pulmonale may ensue, and the management is that of patients with right-sided heart failure and chronic obstructive pulmonary disease.

See Nephrologic Manifestations of Sickle Cell Disease for more information on this topic.

Avascular necrosis of the femoral and humeral heads is treated by not bearing weight at the site. The patient may need to make career and lifestyle adjustments. Occupational retraining and physical therapy may be needed. In many cases, surgical intervention with hip replacement or other orthopedic procedures are needed. Avascular osteonecrosis may result from chronic hypoxia in weight-bearing joints, commonly the femoral head. Joint replacement is often necessary.

SCD can promote psychological problems, such as depression, anxiety, and chronic pain behavior. Counseling is crucial. Ensure an appropriate physician-patient relationship. Anxiolytics and amitriptyline may be used.

Although allogeneic marrow transplantation can cure SCD, the current application of stem cell transplantation (SCT) is complex. Results indicate an event-free survival rate of approximately 84% and a mortality rate of less than 6%.

The risk-benefit ratio has led to the establishment of certain guidelines. Two restrictions limit SCT applicability to approximately 5% of children who qualify through hematologic diagnosis. First, donors must be human leukocyte antigen (HLA) compatible and full siblings (those with sickle trait are acceptable); second, candidates should be limited to patients younger than 16 years with HbSS or HbS–β-0 thalassemia who have evidence of disease severity demonstrated by the following:

• Stroke
• Recurrent acute chest syndrome
• Recurrent severe crisis pain (>2 episodes/y for several years)
• Recurrent priapism
• Impaired neuropsychological function with evidence of cerebral infarction
• Sickle cell nephropathy
• Bilateral proliferative retinopathy and major visual impairment in at least one eye
• Osteonecrosis of multiple joints
• Red cell alloimmunization with more than 2 antibodies during long-term transfusion therapy

A general well-balanced diet is required. No restrictions are necessary.

Although activity is unrestricted, patients may not be able to tolerate vigorous exercise or exertion. Patients with avascular necrosis of the femur may not be able to tolerate weightbearing and may be restricted to bed rest. Patients with chronic leg ulcers may need to restrict activity that involves raising the legs.

Encourage children to participate in physical activities. Because of anemia, they have less stamina than their hematologically healthy playmates. Advise supervising adults of this limitation, particularly teachers and coaches who may require children to run designated distances. Arrange for children to have ready access to liquids and a place to rest and cool off.

Investigational treatments include oral glutamine, nitric oxide inhalation, topical GM-CSF, butyrate, and arginine, as follows:

• Oral glutamine has been used to decrease resting energy expenditure in children^[52]
• Nitric oxide inhalation has been investigated in the treatment of pulmonary hypertension
• Topical GM-CSF has been reported to hasten the healing of leg ulcers
• Butyrate was studied to decrease vaso-occlusive crisis
• Arginine has been proposed to use as a precursor of nitric oxide production

Consultation with a hematologist may be necessary. Each of the protean manifestations of SCD may require assistance from an expert in the involved area. Consultations with pain management experts, social workers, psychiatrists and physical therapists, substance abuse counselors, and vocational rehabilitation workers may be required. Consultation with infectious disease specialists is recommended during febrile illness.

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. Orthopedic consultation is also appropriate if osteomyelitis is suspected. Interventional radiologists may play a role in obtaining a sample to identify the infecting organism in osteomyelitis. Imaging guidance may also allow the drainage of subperiosteal and soft tissue abscesses with the patient under light sedation, thereby avoiding surgery and general anesthesia.

If retinopathy or hyphema is suspected and visual symptoms are present, consultation with an ophthalmologist is warranted. In cases of priapism that does not resolve after 6 hours of hydration and analgesia, consult a urologist for corpus cavernosum aspiration or shunting.

A retina specialist should follow patients to monitor for retinal disease. Uncontrolled secondary glaucoma may require consultation with a glaucoma specialist.

Long-term follow-up is required for patients with SCD. This is a lifelong disorder. The frequency of outpatient visits depends on the patient's clinical status. For patients with minimal symptoms, a visit with blood work every 3-4 months is reasonable. Others may need much more frequent observation.

Educate all patients to recognize signs of infection, increasing anemia, and organ failure. Treat all infections, even trivial ones, very promptly and vigorously. Institute pain medication at the earliest symptoms of a vaso-occlusive crisis. Patients on a chronic transfusion program must adhere to iron chelation therapy. Social services, occupational therapy, and counseling are essential elements in the long-term management of patients with SCD.

Follow-up care depends on involvement with proliferative sickle retinopathy (PSR); once stabilized, visits every 3-6 months may be adequate. When intraocular pressures are stabilized, the patient can be monitored every 6 months

Fluid intake and output should be closely monitored in kidney transplant recipients. In comparison with the general population, these patients have an increased propensity toward intravascular volume depletion, especially secondary to volume losses (through, for example, diarrhea, vomiting, and insensible losses), thereby increasing the risk of an acute sickle cell crisis in patients with SCD.

In patients who have undergone a splenectomy as part of their SCD treatment regimen, there is an increased risk of infection secondary to encapsulated organisms, such as Streptococcus pneumoniae.^[53] Pneumococcal and influenza vaccination is safe in patients with functioning kidney transplants.^{[54, 55, 56]} However, the use of live vaccines is contraindicated due to concomitant immunosuppressive therapy required by these patients.

For infants with sickle cell disease, provide a suggested schedule for well-child visits to ensure that immunizations and other aspects of routine pediatric care are followed. For children aged 1-3 years, consider visits every 3 months for children with hemoglobin (Hb)SS and HbS–β-0 thalassemia, to be certain that parents have sufficient penicillin for prophylaxis and to encourage compliance.