Tracy M. Hagemann and Teresa V. Lewis
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the underlying causes of sickle cell disease (SCD) and their relationship to patient signs and symptoms.
2. Identify the typical characteristics of SCD as well as symptoms that indicate complicated disease
3. Identify the desired therapeutic outcomes for patients with SCD.
4. Recommend appropriate pharmacotherapy and nonpharmacotherapy interventions for patients with SCD.
5. Recognize when chronic maintenance therapy is indicated for a patient with SCD.
6. Describe the components of a monitoring plan to assess effectiveness and adverse effects of pharmacotherapy for SCD.
7. Educate patients about the disease state, appropriate therapy, and drug therapy required for effective treatment and prevention of complications.
KEY CONCEPTS
Sickle cell disease (SCD) is an inherited disorder caused by a defect in the gene for hemoglobin. Patients may have one defective gene (sickle cell trait [SCT]) or two defective genes (SCD).
Although most often seen in persons of African ancestry, other ethnic groups can be affected.
SCD involves multiple organ systems.
Prophylaxis against pneumococcal infection reduces death during childhood.
Hydroxyurea has been shown to decrease the incidence of painful crises. However, the patient population that receives hydroxyurea should be carefully monitored.
Chronic transfusion therapy programs have been shown to be beneficial in decreasing the occurrence of stroke in children with SCD.
Patients with fever greater than 38.5°C (101.3°F) should be evaluated and appropriate antibiotics should include coverage for encapsulated organisms, especially pneumococcal.
Pain episodes can usually be managed at home. Hospitalized patients usually require parenteral analgesics. Analgesic options include opioids, nonsteroidal anti-inflammatory agents, and acetaminophen. The patient characteristics and the severity of the crisis should determine the choice of agent and regimen.
INTRODUCTION
“Sickle cell syndrome” refers to a collection of autosomal recessive genetic disorders that are characterized by the presence of at least one sickle hemoglobin gene (HbS).1,2
Sickle cell disease (SCD) is a chronic illness that is associated with frequent crisis episodes. Acute complications are unpredictable and potentially fatal. Common symptoms include excruciating musculoskeletal pain, life-threatening pneumonia-like illness, cerebrovascular accidents, and splenic and renal dysfunction.2 As the disease progresses, patients may develop organ damage from the combination of hemolysis and infarction. Because of the complexity and severity of SCD, it is imperative that patients have access to comprehensive care with providers who have a good understanding of the countless clinical presentations and the management options of this disorder.
EPIDEMIOLOGY AND ETIOLOGY
Sickle cell trait (SCT) is the heterozygous form (HbAS) of SCD in which a person inherits one normal adult hemoglobin (HbA) gene and one sickle hemoglobin (HbS) gene. These individuals are carriers of the SCT and are usually asymptomatic.2 Symptomatic disease is seen in homozygous and compound heterozygous genotypes of SCD. Sickle cell anemia (SCA) is the homozygous (HbSS) state of SCD.2 It is the most common and severe form of SCD. Compound heterozygosity is seen when individuals inherit one copy of the mutation that causes HbS and one copy of another abnormal hemoglobin gene. Compound heterozygosity may also include the coinheritance of HbS and one of the many different mutations of β-thalasssemia (HbSβ 0-thalassemia and HbS β+ -thalassemia).1-3 SCA affects both males and females equally because it is not a sex-linked disease.
Nine percent of African Americans possess the SCT and 1 in 600 has HbSS.4 Two thousand infants are identified with SCD annually in the United States.5 For every infant diagnosed with SCD, 50 are identified as carriers.5 HbSS (approximately 45%) is the most common genotypic expression, followed by HbSC (approximately 25%), HbSβ+ -thalassemia (approximately 8%), and HbSβ0-thalassemia (approximately 2%). Other variants account for less than 1% of patients.2,5
Having the sickle hemoglobin gene protects heterozygous carriers from succumbing to Plasmodium falciparum (malaria) infection.1 The microorganism cannot parasitize abnormal red blood cells (RBCs) as easily as normal RBCs. Consequently, persons with heterozygous sickle gene (SCT) have a selective advantage in tropical regions where malaria is endemic.
The highest incidence of SCD is seen in those with African heritage, but SCD also affects persons of Indian, Saudi Arabian, Mediterranean, South and Central American, and Caribbean ancestry5,6
Normal adult hemoglobin (HbA) is composed of two α-chains and two β-chains (α2β2).3 A single substitution of the amino acid valine for glutamic acid at position 6 of the β-polypeptide chain is responsible for the production of a defective form of hemoglobin called sickle hemoglobin (HbS).1 Different genetic mutations encode for other hemoglobin variants such as hemoglobin C (HbC). HbC is produced by the substitution of lysine for glutamic acid at the sixth amino acid position in the β-globulin chain.3 The α-chains of HbS, HbA, and HbC are structurally identical. The chemical differences in the β-chain are responsible for RBC sickling and its associated sequelae.
SCA is the homozygous (HbSS) state of SCD in which individuals inherit the mutant hemoglobin gene (HbS) from both parents. The progeny of two carriers will have a 25% probability of having SCD and a 50% risk of being a carrier (Fig. 68–1). β-Thalassemia can be found in conjunction with HbS. Patients with HbSS and HbSβ 0-thalassemia do not have normal β-globulin production and usually have a more severe course than those with HbSC and HbSβ + -thalassemia. SCD involves multiple organ systems, and its clinical manifestations vary greatly between and among genotypes.
FIGURE 68–1. Sickle gene inheritance scheme for both parents with sickle cell trait (SCT). Possibilities with each pregnancy: 25% normal (AA); 50% SCT (AS); 25% sickle cell anemia (SS). (A, normal hemoglobin; S, sickle hemoglobin.) (From Chan CYJ, Moore R. Sickle cell disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008.)
PATHOPHYSIOLOGY
Erythrocyte Physiology
A review of RBC physiology is important to understand the pathophysiology of SCD. Pediatric RBCs possess normal hemoglobin concentrations between 9 and 18.5 g/dL (90–185 g/L or 5.6–11.5 mmol/L), depending on the age of the child.7 Adult RBCs contain 12 to 15.5 g/dL (120–155 g/L or 7.4–9.6 mmol/L) hemoglobin.7 The predominant form of hemoglobin is adult hemoglobin or HbA (96%). Other forms of hemoglobin include HbA2 and fetal hemoglobin (HbF). HbA2 makes up less than 1% of hemoglobin in newborns. In adults, HbA2 constitutes approximately 1.6% to 3.5%.7 Fetal hemoglobin (HbF) is present primarily in fetal RBCs (60–90%), whereas adult RBC’s contain less than 1% HbF.7 HbF is the primary oxygen transport protein in the fetus. After birth, only a small proportion of red cell clones remain to produce HbF. The elasticity of young erythroid cells enables them to deform and squeeze through capillaries (Fig. 68–2). As RBCs age, mean corpuscular hemoglobin concentration (MCHC) increases, deformability decreases, and the cells are removed by the reticuloendothelial system. Impaired circulation, destruction of RBCs, and vascular stasis are three known problems that are primarily responsible for the clinical manifestations of SCD (Fig. 68–3).
Sickle Hemoglobin Polymerization
The primary event in the molecular pathogenesis of SCD involves polymerization of deoxygenated HbS. Since RBCs are packaged with such a high concentration of hemoglobin (32–34 g/dL, 320–340 g/L, or 19.9–21 mmol/L), it is important that the proteins be extremely soluble.1 HbS carries oxygen normally, and when oxygenated, the solubility of HbS and HbA are the same. Once the oxygen is unloaded to the tissues HbS solubility decreases. This promotes hydrophobic interactions between the hemoglobin molecules and polymerization, which leads to the distortion of the RBC into the characteristic crescent or sickle shape.1 Polymerization of deoxy-HbS is influenced by the degree of red cell deoxygenation, MCHC, temperature, intracellular pH, intraerythrocytic HbS concentration, and intracellular HbF concentration.1
FIGURE 68–2. Elongated sickle-shaped and normal discoid-shaped red blood cells. (From Chan CYJ, Moore R. Sickle cell disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005: 1856.)
Viscosity of Erythrocytes and Sickle Cell Adhesion
When HbS becomes reoxygenated, the polymers within the RBCs disappear, and the cells eventually return to normal shape. Vasoocclussion is caused by a combination of factors. Repeated assaults on RBCs from sickling and unsickling can lead to cell membrane damage, loss of membrane flexibility, and rearrangement of surface phospholipids. Damage to cell membranes can interfere with ion transport, leading to loss of potassium and water. This creates dehydrated, dense sickle cells, and irreversible sickle cells (ISCs). ISCs are the densest cells, and they tend to remain sickled even when oxygenated. Rigid ISCs can become trapped in microvasculature, leading to cell fragmentation and chronic hemolysis, thus contributing to short survival of RBCs. The life span of sickled RBCs is markedly shorter (10–20 days) than that of normal RBCs (100–120 days). As intracellular membrane viscosity of HbS-containing RBCs increases, blood viscosity increases, which further contributes to vasoocclussion.8 There is also increasing evidence that suggest sickle cells adhere to vascular endothelium.1,8 The combined effects of decreased RBC deformability, slow transit through microcirculation, and adhesion to vascular endothelium contribute to obstruction of small and sometimes large blood vessels. The resulting local tissue hypoxia can accentuate the pathologic process of SCD.
Protective Hemoglobin Types
Fetal hemoglobin binds oxygen more tightly than HbA, and it has a decreased propensity to sickling. HbA2 also possesses this characteristic but to a lesser extent. RBCs that contain HbF sickle less readily than cells without. ISCs are found to have low HbF concentrations. In some patients, higher HbF may ameliorate the disease.
FIGURE 68–3. Pathophysiology of SCD. (Arg, arginine; ET-1, endothelin-1; Hb, hemoglobin; NO, nitric oxide; NOS, nitrous oxide synthase; VCAM-1, vascular cell adhesion molecule 1; XO, xanthine oxidase.) (From Kato GJ, Gladwin MT. Sickle cell disease. In: Hall JB, Schmidt GA, Wood LDH, (eds.). Principles of Critical Care, 3rd ed. New York: McGraw-Hill, 2005:1658.)
Clinical Presentation and Diagnosis of SCT
General
• Generally asymptomatic
Symptoms
• Females may have frequent urinary tract infections
Signs
• Microscopic hematuria occurs rarely
• Gross hematuria may occur spontaneously or with heavy intensity exercise
Laboratory Tests
• Normal Hgb values
Other Pathophysiologic Effects
Other factors may be responsible for the pathogenesis of some of the clinical features of SCD. Sickle cells can obstruct blood flow to the spleen leading to functional asplenia. Impaired splenic function can increase the propensity to infection by encapsulated organisms, particularly Streptococcus pneumoniae.1 Additionally, coagulation abnormalities are not uncommon since almost every component of hemostasis is altered in SCD.
Clinical Presentation and Diagnosis of SCD
General
• Indentified by neonatal screening before 2 months of age
Symptoms
• Painful vasoocclusive crises are the hallmark of SCD
• Dactylitis (hand-foot syndrome) before age 1 year
• May develop infarction of the spleen, liver, bone marrow, kidney, brain, and lungs
• Gallstones
• Priapism in males
• Slow healing lower extremity ulcers after trauma or infection
• Weakness, fatigue
Signs
• Chronic hemolytic anemia is common
• Enlargement of spleen, and heart
• Scleral icterus
Laboratory Tests
• Hgb 7 to 10 g/dL (70-100 g/L or 4.3-6.2 mmol/L)
• Low HgF and increased reticulocytes, platelets, and WBCs
• Presence of sickled cells on blood smear (see Fig. 68–2)
• Neonatal screening: hemoglobin electrophoresis, isoelectric focusing, or DNA analysis
TREATMENT
Desired Outcomes
Multidisciplinary, regularly scheduled care is required over the lifetime of the SCD patient with the goal of reduction of complications and hospitalizations. Comprehensive care should include medical, educational, and psychosocial aspects as well as genetic and medication counseling.
Therapeutic interventions for SCD should be targeted at preventing and/or minimizing the symptoms related to the disease and its complications. The goals of treatment are to reduce or eliminate the patient’s symptoms; decrease the frequency of sickle crises, including vasoocclusive pain crises; prevent the development of complications; and maintain or improve the quality of life through decreased hospitalizations and decreased morbidity. Specific therapeutic options may:
• Maintain or increase the hemoglobin level to the patient’s baseline
• Increase the HbF concentration
• Decrease the HbS concentration
• Prevent infectious complications
• Prevent or effectively manage pain
• Prevent CNS damage, including stroke
General Approach to Treatment
Patients should be educated to recognize the signs and symptoms of complications that would require urgent evaluation. Patients and parents of children with SCD should be educated to read a thermometer properly and to seek immediate medical care when a fever develops or signs of infection occur. With acute illnesses, prompt evaluation is important as deterioration may occur rapidly. Fluid status should be monitored to avoid dehydration or overhydration, both of which may worsen complications of SCD. Patients in acute distress should main -tain oxygen saturation at 92% or at their baseline. Any supple-mental oxygen requirements should be evaluated.5,9
Nonpharmacologic Therapy
Patients should avoid smoking and excessive alcohol intake. Patients with SCD should maintain adequate hydration in order to help decrease blood viscosity, and should be educated to avoid extreme temperature changes and to dress properly in hot and cold weather. Physical exertion that leads to complications should be avoided.5 Regular exams, including ophthalmic, renal, pulmonary, and cardiac function, are required to monitor for organ damage. A treatment overview is shown in Table 68–1.
Pharmacologic Therapy
Health Maintenance
Immunizations
Children with SCD should receive the required immunizations as recommended by the American Academy of Pediatrics and the Advisory Committee on Immunization Practices.10 Additionally, influenza vaccine should be administered yearly to SCD patients 6 months of age and older, including adult patients. Any SCD patient who is scheduled for splenectomy should receive the vaccine for meningococcal disease if over 2 years of age.11
Because patient with SCD have impaired splenic function they are less adequately protected against encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae and Salmonella. The use of pneumococcal vaccine in SCD patients has dramatically decreased the rates of morbidity and mortality; however, there are still groups of SCD children who continue to have high rates of invasive pneumococcal infections.12Infection is the leading cause of death in children younger than 3 years of age.13,14 Two pneumococcal vaccines are available. The 7-valent conjugate vaccine (PCV 7: Prevnar) is indicated for infants and children and provides good protection against the seven most common isolates seen in this age-range. Administer the first dose of PCV 7 between 6 weeks and 6 months of age, followed by two additional doses at 2 month intervals and a fourth dose at 12 to 15 months of age. The 23-valent polysaccharide vaccine (PPV 23: Pneumovax 23) is indicated for children over 2 years of age and adults. Because PPV 23 is a polysaccharide vaccine, children less than two years of age do not respond well. PPV 23 contains the 23 most common isolates of S. pneumoniae seen in older children and adults. Because of the difference serotypes seen in the two vaccines, it is recommended that SCD children receive both vaccines, with a dose of PPV 23 administered after the child turns 2 years of age. The dose of PPV 23 should be separated from the last dose of PCV 7 by at least 2 months. An additional dose of PPV 23 should be considered in children 3 to 5 years of age to ensure antibody response. All adults with SCD should be vaccinated once with PPV 23 also. Because some children fall behind on their childhood vaccinations, a catchup schedule is presented in Table 68–2.11
Table 68–1 Management of SCD
Penicillin Children with SCD should receive prophylactic infections. Penicillin V potassium is typically initiated at age 2 months with a dose of 125 mg orally twice daily until age 3 years, then 250 mg orally twice daily until 5 years of age. The intramuscular use of benzathine penicillin 600,000 units every 4 weeks from age 6 months to 6 years is also an option for noncompliant patients. Penicillin allergic patients may receive erythromycin 10 mg/kg twice daily. Penicillin prophylaxis usually is not continued in children over the age of 6 years, but may be considered in patients with a history of invasive pneumococcal infection or surgical splenectomy.5,15–17
Table 68–2 Pneumococcal Immunization for Children With SCD
Patient Encounter 1
An 18-month-old female is presenting for a routine check-up. She was diagnosed with sickle cell anemia at birth, identified through neonatal screening. Today, her hemoglobin is 8.6 g/dL (86 g/L or 5.3 mmol/L) and she is afebrile.
What acute complications is she at risk for developing?
What preventative treatment should she receive?
What additional information do you need to know before creating a plan for this patient?
Folic Acid
Folic acid supplementation with 1 mg daily is generally recommended in adult SCD patients, women considering pregnancy, and any SCD patient with chronic hemolysis.5 Because of accelerated erythropoiesis, these patients have an increased need for folic acid. There are conflicting studies in the SCD population, especially among infants and children, but if the child has chronic hemolysis, supplementation is recommended.18
Fetal Hemoglobin Inducers
Fetal hemoglobin (HbF) induction in patients with SCD, especially those with frequent crises, has been shown to decrease RBC sickling and RBC adhesion. A direct relationship between HbF concentrations and the severity of disease have been demonstrated in studies.2
Hydroxyurea
Hydroxyurea is a riboneucleotide reductase inhibitor that prevents DNA synthesis and traditionally has been used in chemotherapy regimens. Studies in the 1990s also found that hydroxyurea increases HbF levels as well as increasing the number of HbF-containing reticulocytes and intracellular HbF. Other beneficial effects of hydroxyurea include antioxidant properties, reduction of neutrophils and monocytes, increased intracellular water content leading to increased red cell deformability, decreased red cell adhesion to endothelium, and increased levels of nitric oxide, which is a regulator involved in physiologic disturbances.19
Hydroxyurea reduced the frequency of hospitalizations and the incidences of pain, acute chest syndrome, and blood transfusions by almost 50% in a landmark trial in adult SCD patients with moderate to severe disease.Hemoglobin and HbF concentrations increased and hemolysis decreased.19 A follow-up study demonstrated a 40% reduction in mortality over a 9-year period in patients continuing to receive hydroxyurea.20 Not all patients responded equally therefore hydroxyurea may not be the best option for all patients.
The use of hydroxyurea in children and adolescents with SCD has been investigated and similar results were reported as in adult trials with no adverse effects on growth and development.5,21,22 Hydroxyurea is recommended as an option for children with moderate to severe SCD.23
The most common adverse effect of hydroxyurea in reported studies is myelosuppression. Long-term adverse effects are unknown but myelodysplasia, acute leukemia, and chronic opportunistic infections have been reported.24Hydroxyurea is teratogenic in high doses in animal studies and this is a concern, which should be addressed with patients. Normal pregnancies with no birth defects have been reported in some women receiving hydroxyurea, but close monitoring and weighing risk versus benefit to the patient are vitally important. Hydroxyurea is excreted in breast milk and should be avoided in lactating mothers.9
Hydroxyurea should be considered in SCD with frequent vasoocclusive crises, severe symptomatic anemia, repeated history of acute chest syndrome (ACS), or other history of severe vasoocclusive crisis (VOC) complications.5The prevention of organ damage or reversal of previous damage has not been shown to occur with chronic use of hydroxyurea.20 The goals of therapy with hydroxyurea are to decrease the acute complications of SCD, improve quality of life, and reduce the number and severity of pain crises.
Hydroxyurea is available in 200-, 300-, 400-, and 500-mg capsules. Extemporaneous liquid preparations can be prepared for children who cannot swallow capsules. Doses should start at 10 to 15 mg/kg daily in a single oral dose, which can be increased after 8 to 12 weeks if blood counts are stable and there are no side effects. Individualize the dosage based on the patient’s response and the toxicity seen. With close monitoring, doses can be increased 5 mg/kg/day up to 35 mg/kg daily.19 In patients with renal failure, dosing of hydroxyurea will need to be adjusted according to the creatinine clearance, as shown in Table 68–3.
Closely monitor patients for efficacy and toxicity while they are receiving hydroxyurea. Monitor mean corpuscular volume (MCV), since it increases as the level of HbF increases. If the MCV does not increase with hydroxyurea use, the marrow may be unable to respond, the dose may not be adequate, or the patient may be noncompliant.9 HbF levels can also be monitored to assess response with a goal of increasing HbF to 15% to 20%. Assess blood counts every 2 weeks during dose titration and then every 4 to 6 weeks once the dose is stabilized. Temporary discontinuation of therapy is warranted if hemoglobin level is less than 5 g/dL (50 g/L or 3.1 mmol/L), absolute neutrophil count is less than 2 × 103/mm3 (2 × 109/L) platelets are less than 80 × 103/mm3 (80 × 109/L), or the reticulocytes are less than 80 × 103/mm3 (80 × 109/L) if the hemoglobin is less than 9 g/dL (90 g/L or 5.6 mmol/L). Monitor for increases in serum creatinine and transaminases. Once the patient’s blood counts have returned to baseline, hydroxyurea may be restarted with a dose that is 2. 5 to 5 mg/kg less than the dose associated with the patient’s toxicity. Doses may then be increased by 2. 5 to 5 mg/kg daily after 12 weeks with no toxicity.
Administer prophylactic folic acid supplementation to SCD patients receiving hydroxyurea, because folate deficiency may be masked by the use of hydroxyurea.
Table 68–3 Dosage Adjustments for Renal and Hepatic Dysfunction
5-Aza-2’-Deoxycytine (Decitabine)
For patients who do not respond to hydroxyurea, 5-azacytidine and 5-aza-2’-deoxycytidine (decitabine) may be useful. Both induce HbF by inhibiting methylation of DNA, preventing the switch from y - to Δ-globin production. Decitabine appears to be safer and more potent than 5-azacytadine. In a small study in adults refractory to hydroxyurea, decitabine 0.2 mg/kg subcutaneously one to three times weekly was associated with an increase in HbF in all patients. Additionally, RBC adhesion was reduced. Neutropenia was the only significant toxicity reported.31
Combinations of HbF Inducers
Very limited information is available on the use of combination therapy for potentiation of HbF production. Erythropoietin has shown inconsistent results in small numbers of patients. When used with hydroxyurea, erythropoietin has been shown to increase HbF to a greater extent than hydroxyurea alone; and although more studies are needed, this may provide an option for patients who do not respond to hydroxyurea alone.9
Chronic Transfusion Therapy
Chronic transfusion therapy is warranted to prevent serious complications from SCD, including stroke prevention and recurrence. Especially in children, chronic transfusions have been shown to decrease stroke recurrence from approximately 50% to 10% over 3 years. Without chronic transfusions, approximately 70% of ischemic stroke patients will have another stroke. Chronic transfusion therapy also may be used to prevent vasoocclusive pain and ACS, as well as prevent progression of organ damage. Patients receiving chronic transfusion therapy report increased energy levels, improved quality of life, and better exercise tolerance. Patients in whom chronic transfusion therapy should be considered, include those with severe or recurrent ACS, debilitating pain, splenic sequestration, recurrent priapism, chronic organ failure, transient ischemic attacks, abnormal transcranial Doppler studies, intractable leg ulcers, severe chronic anemia in the presence of cardiac failure, and complicated pregnancies.5,9
Patient Encounter 2
LK is a 15-year-old female with a history of sickle cell disease (HbS).
PMH: Cholecystectomy at age 11 years; admitted for vasoocclusive crises five times over the past year; acute chest syndrome at age 13 and 14; immunizations up-to-date; multiple blood transfusions
FH: Father with SC trait; mother with SCD
SH: Student in the 9th grade; denies alcohol or drug use; is sexually active
Meds: Lortab 7.5 mg tablets orally every 4 to 6 hours as needed for pain; ibuprofen 600 mg orally three times a day as needed for pain; Folic acid 1 mg orally daily
The medical team wants to start LK on hydroxyurea.
Is she a candidate for hydroxyurea? Why or why not?
What initial laboratory work is required before initiating hydroxyurea?
Identify treatment goals for hydroxyurea in LK.
What is the initial dose and how will you monitor for efficacy?
What patient counseling is needed?
How will you monitor for toxicity?
Several methods of transfusion may be used, including simple transfusion, exchange transfusion, or erythrocytapher-esis. The goal of chronic transfusion therapy is to maintain the HbS level at less than 30% (0.30) of total hemoglobin concentration. Transfusions are usually administered every 3 to 4 weeks depending on the HbS concentration. For secondary stroke prevention, current studies have indicated that lifelong transfusion may be required, with increased incidence of recurrence once transfusions are stopped.5
The benefits of transfusion should be weighed with the risks. Risks associated with transfusions include allo-immunization (sensitization to the blood received), hyperviscosity, viral transmission, volume overload, iron overload, and transfusion reactions. Approximately 18% to 30% of SCD patients who receive transfusions will experience alloimmunization, which can be minimized by the use of leukocyte-reduced RBCs or HLA-matched units. Viral transmission is still a concern, despite increased screening of blood donors and units. While the risk of contraction of AIDS has decreased dramatically, hepatitis C remains a concern. All SCD patients should be vaccinated for hepatitis A and B, and should be serially monitored for hepatitis C and other infections. Parvovirus occurs in 1 of every 40,000 units of RBCs and can be associated with acute anemia and multiple sickle cell complications.5 Iron overload remains a concern among those patients maintained on chronic transfusions for greater than 1 year. Counsel patients to avoid excessive dietary iron and monitor serum ferritin regularly. Chelation therapy with deferoxamine or deferasirox should be considered when the serum ferritin level is greater than 1,500 to 2,000 ng/mL (1,500–2,000 mcg/L). Deferoxamine should be initiated at 20 to 40 mg/kg daily (to a maximum of 1–2 g/day) over 8 to 12 hours subcutaneously, and has been associated with growth failure.5 Monitor children receiving deferoxamine for adequate growth and development on a regular basis. Deferasirox should be initiated at 20 mg/kg daily, and is available in a tablet that should be dispersed in water, orange juice, or apple juice and taken orally 30 minutes before food.32,33 Monitor all chelation patients for auditory and ocular changes on a yearly basis. Exchange transfusions may also be helpful in cases of iron overload.
Sickle cell hemolytic transfusion reaction syndrome is a unique problem in SCD patients. Due to alloimmunization, an acute or delayed transfusion reaction may occur. Delayed reactions typically occur 5 to 20 days post-transfusion. Alloantibodies and autoantibodies resulting from previous transfusions can trigger the reaction, in which patients develop symptoms suggestive of a pain crisis or worsening symptoms if they are already in crisis. A severe anemia after transfusion also may occur due to a rapid decrease in hemoglobin and hematocrit, along with a suppression of erythropoiesis. Further transfusions may worsen the clinical picture due to autoimmune antibodies. Recovery may occur only after ceasing all transfusions, and is evidenced by a gradual increase in hemoglobin with reticulocytosis5,9
Allogeneic Hematopoietic Stem Cell Transplant
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potential cure for SCD. The best candidates are children with SCD who are younger than 16 years of age with severe complications, who have an identical HLA-matched donor, usually a sibling. The transplant related mortality rate is between 5% and 10% and graft rejection is approximately 10%. Other risks include secondary malignancies, development of seizures or intracranial bleeding, and infection in the immediate post-transplant period.5,34,35
Experience with HSCT in adult patients with SCD is very limited. Umbilical cord blood and hematopoietic cells from nonmatched donors are potential alternatives in some patients, but use is limited.5,35
Acute Complications
Transfusions for Acute Complications Red cell transfusion is indicated in patients with acute exacerbations of baseline anemia; in cases of severe vasoocclusive episodes, including ACS, stroke, and acute multiorgan failure; and in preparation for procedures that will require the use of general anesthesia or ionic contrast products. Transfusions also may be useful in patients with complicated obstetric problems, refractory leg ulcers, refractory and prolonged pain crises, or severe priapism. Hyperviscosity may occur if the hemoglobin level is increased to greater than 10 to 11 g/dL (100–110 g/L or 6.2–6.8 mmol/L). Volume overload leading to congestive heart failure is more likely to occur if the anemia is corrected too rapidly in patients with severe anemia, and should be avoided.5,9
Infection and Fever 
Any fever greater than 38.5°C (101.3°F) in a SCD patient should be immediately evaluated, and the patient should have a blood culture drawn and be started on antibiotics that provide empirical coverage for encapsulated organisms.9
Patients who should be hospitalized include the following:
• Infants younger than 1 year of age
• Patients with a previous sepsis or bacteremia episode
• Patients with temperatures in excess of 40°C (104°F)
• Patients with WBC counts greater than 30 × 103/mm3 (30 × 109/L) or less than 0.5 × 103/mm3 (0.5 × 109/L) and/or platelets less than 100 × 103/mm3 (100 × 10 9/L) with evidence of other acute complications
• Acutely ill-appearing individuals
Broad IV antibiotic coverage for the encapsulated organisms can include ceftriaxone or cefotaxime. For patients with true cephalosporin allergy, clindamycin may be used. If staphylococcal infection is suspected due to previous history or the patient appears acutely ill, vancomycin should be initiated. Macrolide antibiotics, such as erythromycin or azithromycin, may be initiated if mycoplasma pneumonia is suspected. While the patient is receiving broad-spectrum antibiotics, their regular use of penicillin for prophylaxis can be suspended. Fever should be controlled with acetaminophen or ibuprofen. Because of the risk of dehydration during infection with fever, increased fluid requirements may be needed.5,9
Clinical Presentation and Diagnosis of Infection in SCD
General
• Patients may become acutely distressed very rapidly
• A low threshold to begin empiric therapy is recommended
Symptoms
• Patients may complain of lethargy, nausea, cough, or a general “unwell” feeling
Signs
• Temperature greater than 38.5°C (101.3°F)
Laboratory Tests
• CBC with reticulocyte count
• Cultures (urine, blood, and throat)
• Lumbar puncture if toxic-looking or signs of meningitis
• Urinalysis
• Chest x-ray
Potential Pathogens
• Streptococcus pneumoniae (most common), Haemophilusinfluenzae, Salmonella, Mycoplasma pneumoniae, Chlamydia, and viruses (parvovirus B19)
Bone infarcts or sickling in the periosteum usually is indicated by pain and swelling over an extremity. Osteomyelitis also should also be considered. Salmonella species are the most common cause of osteomyelitis in SCD children, followed by Staphylococcus aureus.9 Select an appropriate antibiotic to cover the suspected organisms empirically.
Cerebrovascular Accidents
Acute neurologic events, such as stroke, will require hospitalization and close monitoring. Patients should have physical and neurologic examinations every 2 hours.9 Acute treatment may include exchange transfusion or simple transfusion to maintain hemoglobin at around 10 g/dL (100 g/L or 6.2 mmol/L) and HbS concentration at less than 30%. Patients with a history of seizure may need anticonvulsants, and interventions for increased intracranial pressure should be initiated if necessary. Children with history of stroke should be initiated on chronic transfusion therapy. Adults presenting with ischemic stroke should be considered for thrombolytic therapy if it has been less than 3 hours since the onset of symptoms.5,9
Clinical Presentation and Diagnosis of Stroke in SCD
General
• Most common cause is cerebrovascular occlusion
• Initial episode most often occurs during first 10 years of life
• Silent infarcts seen on MRI have been reported in 22% of patients and may be associated with increased risk of stroke and decreased neurocognitive function
Symptoms
• Patients may present with headache, vomiting, stupor, hemiparesis, aphasia, visual disturbances and seizure
Evaluation
• CT scan and MRI for acute event
• Magnetic resonance angiography for asymptomatic infarction
• Transcranial Doppler to detect abnormal velocity and identify high-risk patients
• Electroencephalography if there is history of seizure
• Chest x-ray
Early detection of ischemic stroke can be done with the use of transcranial Doppler ultrasonography. In the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study, screening with this method followed by chronic transfusion therapy significantly reduced the incidence of stroke.36 Screening is recommended in all patients over the age of two.
Acute Chest Syndrome
ACS will require hospitalization for appropriate management of symptoms and to avoid complications. Patients should be encouraged to use incentive spirometry at least every 2 hours. Incentive spirometry helps the patient take long, slow breaths to increase lung expansion. Appropriate management of pain is important, but analgesic-induced hypoventilation should be avoided. Patients should maintain appropriate fluid balance because overhydration can lead to pulmonary edema and respiratory distress. Infection with gram-negative, gram-positive, or atypical bacterial is common in ACS and early use of broad-spectrum antibiotics, including a macrolide, quinolone, or cephalosporin is recommended. Fat emboli, from infarction of the long bones, may lead to ACS. Oxygen therapy should be utilized in any patient presenting with respiratory distress or hypoxia. Oxygen saturations, measured by pulse oximeter, should be maintained at 92% or above. Transfusions are often indicated and patients who present with wheezing may require inhaled bronchodilators.5,37,38
Clinical Presentation and Diagnosis of ACS in SCD
General
• Occurs in 15% to 43% of patients and is responsible for 25% of deaths
• Risk factors include young age, low HbF level, high Hgb and WBCs, winter seasons, reactive airway disease
• Recurrences are up to 80% and can lead to chronic lung disease
Symptoms
• Patients may complain of cough, fever, dyspnea, chest pain
Signs
• Temperature greater than 38.5°C (101.3°F)
• Hypoxia
• New infiltrate on chest x-ray
Laboratory Tests
• Complete blood count with reticulocyte
• Blood gases
• Oxygen saturation
• Cultures (blood and sputum)
Other
• Closely monitor pulmonary status
The use of corticosteroids is controversial. While they may decrease the inflammation and endothelial cell adhesion seen with ACS, their use has also been associated with higher readmission rates for other complications. Tapered corticosteroids, nitric oxide therapy, and l-arginine are being evaluated for use in ACS in studies.37,39
Priapism
By age 18, approximately 90% of SCD males will have had at least one episode of priapism. Stuttering priapism, where erection episodes last anywhere from a few minutes to less than 2 hours, resolves spontaneously. Erections lasting more than 2 hours should be evaluated promptly. Goals of therapy are to provide pain relief, reduce anxiety, provide detumescense, and preserve testicular function and fertility. Initial treatment should include aggressive hydration and analgesia. Transfusion may or may not be helpful, but should be considered in anemic patients. Avoid the use of ice packs due to the risk of tissue damage.5,9
Both vasoconstrictors and vasodilators have been used in the treatment of priapism. Vasoconstrictors are thought to work by forcing blood out of the cavernosum and into the venous return. Aspiration of the penile blood followed by intracavenous irrigation with epinephrine (1:1,000,000 solution) has been effective with minimal complications.40 In severe cases, surgical intervention to place penile shunts has been used, but there is a high failure rate, and the risk of complications, from skin sloughing to fistulas, limits its use.
Clinical Presentation and Diagnosis of Priapism in SCD
General
• Mean age of initial episode is 12 years of age
• Most males with SCD will have one episode by age 20
• Repeated episodes can lead to fibrosis and impotence
Symptoms
• Patients may complain of painful and unwanted erection lasting anywhere from less than 2 hours (stuttering type) to more than 2 hours (prolonged type)
Signs
• Urinary obstruction
Laboratory Tests
• CBC with reticulocyte
Other
• Monitor for duration of episode
• Prolonged episodes should be considered medical emergencies
Pseudoephedrine dosed at 30 to 60 mg/day taken at bedtime, has been used to prevent or decrease the number of episodes of priapism.5 Terbutaline 5 mg has been used orally to prevent priapism with mixed results.41,42Leuprolide, a gonadotropin-releasing hormone, also has been used for this indication. Hydroxyurea may be helpful in some patients. The use of antiandrogens is under investigation.5,9
Treatment of Acute Complications
Aplastic Crisis
Most patients in aplastic crisis will recover spontaneously and therefore treatment is supportive. If anemia is severe or symptomatic, transfusion may be indicated. Infection with human parvovirus B19 is the most common cause of aplastic crisis. Isolate infected patients, because parvovirus is highly contagious. Pregnant individuals should avoid contact with infected patients because midtrimester infection with parvovirus may cause hydrops fetalis and still birth.5,9
Sequestration Crisis
RBC sequestration in the spleen in young children may lead to a rapid drop in hematocrit, resulting in hypovolemia, shock, and death. Treatment is RBC transfusion to correct the hypovolemia, as well as broad-spectrum antibiotics because infections may precipitate the crisis.5,9
Recurrent episodes are common and can be managed with chronic transfusion and splenectomy. Observation is used commonly in adults because their episodes are milder. Splenectomy is usually delayed until after 2 years of age to lessen the risk of postsplenectomy septicemia. Patients with chronic hypersplenism should be considered for splenectomy.5,43
Clinical Presentation and Diagnosis of Acute Aplastic Crisis in SCD
General
• Transient suppression of RBC production in response to bacterial or viral infection
• Most commonly due to infection with parvovirus B19
Symptoms
• Patients may complain of headache, fatigue, dyspnea, pallor, or fever
• Patients may also complain of upper respiratory or GI infection symptoms
Signs
• Temperature greater than 38.5°C (101.3°F) may occur
• Hypoxia
• Tachycardia
• Acute decrease in Hgb with decreased reticulocyte count
Laboratory Tests
• CBC with reticulocyte
• Chest x-ray
• Parvovirus titers
• Cultures (blood, urine, and throat)
Vasoocclusive Pain Crisis
The mainstay of treatment for vasoocclusive crisis includes hydration and analgesia (Table 68–4). Pain may involve the extremities, back, chest, and abdomen. Patients with mild pain crisis may be treated as outpatients with rest, warm compresses to the affected (painful) area, increased fluid intake, and oral analgesia. Moderate to severe crises should be hospitalized. Infection should be ruled out because it may trigger a pain crisis, and any patient presenting with fever or critical illness should be started on empirical broad-spectrum antibiotics. Patients who are anemic should be transfused to their baseline. IV or oral fluids at 1.5 times maintenance is recommended. Close monitoring of the patient’s fluid status is important to avoid overhydration, which can lead to ACS, volume overload, or heart failure.5,9
Aggressive pain management is required in patients presenting in pain crisis. Assess pain on a regular basis (every 2–4 hours) and individualize management to the patient. The use of pain scales may help with quantifying the pain rating. Obtain a good medication history of what has worked well for the patient in the past. Use acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) for treatment of mild to moderate pain. Patients with bone or joint pain, who require IV medications may be helped by the use of ketorolac, an injectable NSAID. Because of the concern for side effects, including GI bleeding, ketorolac should be used only for a maximum of 5 consecutive days. Monitor for the total amount of acetaminophen given daily, because many products contain acetaminophen. Maximum daily dose of acetaminophen for adults is 4 g/day, and for children, five doses over a 24-hour period.44Add an opioid if pain persists or if pain is moderate to severe in nature. Combining an opioid with an NSAID can enhance the analgesic effects without increasing adverse effects.45–47
Clinical Presentation and Diagnosis of Sequestration Crisis in SCD
General
• Acute exacerbation of anemia due to sequestration of large blood volume by the spleen
• More common in patients with functioning spleens
• Onset often associated with viral or bacterial infections
• Recurrence is common and can be fatal
Symptoms
• Sudden onset of fatigue, dyspnea, and distended abdomen
• Patients may present with vomiting and abdominal pain
Signs
• Rapid decrease in Hgb and Hct with elevated reticulocyte count
• Splenomegaly
• May exhibit hypotension and shock
Evaluation
• Vital signs
• Spleen size changes
• Oxygen saturations
• CBC with reticulocyte count
• Cultures (blood, urine, throat)
Clinical Presentation and Diagnosis of Vasoocclusive Crisis in SCD
General
• Most often involves the bones, liver, spleen, brain, lungs, and penis
• Precipitating factors include: infection, extreme weather conditions, dehydration, and stresses
• Recurrent acute crises result in bone, joint, and organ damage and chronic pain
Symptoms
• Patients may complain of deep throbbing pain, local tenderness
Signs
• Erythema and swelling of painful area
• Dactylitis in young infants
• Temperature greater than 38.5°C (101.3°F)
• Leukocytosis
Laboratory tests
• CBC with reticulocyte
• Urinalysis
• Abdominal studies (if symptoms exist)
• Cultures (blood and urine)
• Liver function tests and bilirubin
• Chest x-ray
Severe pain should be treated with an opioid such as morphine, hydromorphone, methadone or fentanyl. Moderate pain can be effectively treated in most cases with a weak opioid such as codeine or hydrocodone, usually in combination with acetaminophen. Meperidine should be avoided because of its relatively short analgesic effect and its toxic metabolite, normeperidine. Normeperidine may accumulate with repeated dosing and can lead to CNS side effects including seizures.
IV opioids are recommended for use in treatment of severe pain because of their rapid onset of action and ease in titration. Intramuscular injection should be avoided. Analgesia should be individualized and titrated to effect, either by scheduled doses or continuous infusion. The use of continuous infusion will avoid the fluctuations in blood levels between doses that is seen with bolus dosing. As needed dosing of analgesia is only appropriate for breakthrough pain or uncontrolled pain. Patient-controlled analgesia (PCA) is commonly used and allows the patient to have control over his or her analgesic breakthrough dosing. As the pain crisis resolves, the pain medications can be tapered. Physical therapy and relaxation therapy can be helpful adjuvants to analgesia.45–48
Tolerance to opioids is seen when patients have had continuous long-term use of the medications and can be managed during acute crises by using a different potent opioid or using a larger dose of the same medication. Adverse effects associated with the use of opioids include respiratory depression, itching, nausea and vomiting, constipation, and drowsiness. Patients on continuous infusions of opioids should be on continuous pulse oximeter to assess oxygen saturations. Monitor the patient for oxygen saturations less than 92%. Oxygen should be administered as needed to keep the saturations above 92%. Itching can be managed with an antihistamine such as diphenhydramine. Nausea and vomiting can be treated and managed with the administration of antiemetics such as promethazine or the 5HT3 antagonists, but the use of promethazine is contraindicated in children younger than 2 years of age. Assess stool frequency in all patients on a continuous opioid, and start stool softeners or laxatives as needed. Excessive sedation is difficult to control and the concurrent use of an opioid with diphenhydramine or other sedative medications can exacerbate the drowsiness, leading to hypoxemia. A continuous very low dose of naloxone, an opioid antagonist, has been used in some cases where the adverse effects such as itching are unbearable.49
Table 68–4 Management of Acute Pain of SCD
Principles
• Treat underlying precipitating factors
• Avoid delays in analgesia administration
• Use pain scale to assess severity
• Choice of initial analgesic should be based on previous pain crisis pattern, history of response, current status, and other medical conditions
• Schedule pain medication; avoid as-needed dosing
• Provide rescue dose for breakthrough pain
• If adequate pain relief can be achieved with one or two doses of morphine, consider outpatient management with a weak opioid; otherwise hospitalization is needed for parenteral analgesics
• Frequently assess to evaluate pain severity and side effects; titrate dose as needed
• Treating adverse effects of opioids is part of pain management
• Consider nonpharmacologic intervention
• Transition to oral analgesics as the patient improves; choose an oral agent based on previous history, anticipated duration, and ability to swallow tablets; if sustained-release products are used, a fast-release product is also needed for breakthrough pain
Analgesic Regimens
Mild to moderate pain:
Acetaminophen with codeine
• Dose based on codeine—children: 1 mg/kg per dose every 6 hours; adults: 30–60 mg/dose
Hydrocodone + acetaminophen:
• Dose based on hydrocodone—children: 0.2 mg/kg per dose every 6 hours; adults: 5–10 mg/dose
Anti-inflammatory agents
• Use with caution in patients with renal failure (dehydration) and bleeding
• Ibuprofen: children: 10 mg/kg every 6–8 hours; adults: 200–400 mg/dose
• Naproxen: 5 mg/kg every 12 hours; adults: 250–500 mg/dose
• Ibuprofen + hydrocodone: Each tablet contains 200 mg ibuprofen and 7.5 mg hydrocodone per tablet; only for older children who can swallow tablets
Moderate to severe pain:
Morphine—children: 0.1–0.15 mg/kg per dose every 3–4 hours; adults: 5–10 mg/dose
• Continuous infusion: 0.04–0.05 mg/kg/h; titrate to effect
Hydromorphone—children: 0.015 mg/kg per dose every 3–4 hours; adults: 1.5–2 mg/dose
• Continuous infusion: 0.004 mg/kg/h; titrate to effect
IV anti-inflammatory agents:
• Ketorolac: 0.5 mg/kg up to 30 mg/dose every 6 hours Patient-controlled analgesics:
• Morphine: 0.01–0.03 mg/kg/h basal; demand 0.01–0.03 mg/kg every 6–10 minutes; 4 hours lockout 0.04–0.06 mg/kg
• Hydromorphone: 0.003–0.005 mg/kg/h basal; demand 0.003–0.05 mg/kg every 6–10 minutes; 4 hours lock out 0.4–0.6 mg/kg
Patient Encounter 3
CC: “My right leg and lower back hurt badly”
HPI: CD is a 21-year-old African American male diagnosed with sickle cell disease at birth. He has had repeated pain crises (average of about two per year) and presents today with another. He started feeling ill yesterday and this morning woke up with increased pain and a cough.
PMH: Frequent pain crises, acute chest syndrome last year, priapism
FH: Mother with sickle cell trait, Father with sickle cell disease. Father died at age 36 from stroke. Has an older brother with sickle cell disease and a younger sister with sickle cell trait.
SH: CD is a college student. He lives in the dorms. Enjoys basketball.
PE: Wt 64 kg (14 lb), ht 180 cm (6 ft), BP 130/80, HR 90, RR
30, temp 40°C (104°F)
Lungs: decreased breath sounds in bases
Skin: Warm, dry, tender, and increased warmth in right leg, nailbeds dusky, poor capillary refill
HEENT: Sclera slightly yellow
Meds: Tylenol #3, two tablets orally every 4 to 6 hours as needed for pain; pseudoephedrine 30 mg orally twice daily
Allergies: NKDA
Lab: All within normal limits except; Hemoglobin: 6.2 g/dL; hematocrit: 30 g/dL; WBC: 20,000/mm3; Total bilirubin: 2. 2 mg/dL
Based on the information presented, create a care plan for this patient’s vasoocclusive crisis. Your plan should include the following:
Statement of the drug-related needs and/or problems
Goals of therapy
Patient-specific, detailed therapeutic plan
Plan for follow-up and monitoring to determine whether the goals have been achieved and adverse effects avoided.
Table 68–5 Chronic Complications of SCD
OUTCOME EVALUATION
SCD treatment and prevention are considered successful when complications are minimized. The major outcome parameters are a decrease in morbidity and mortality, measured by the number of hospitalizations, and the extent of end-organ damage seen over time. Today, with longer survival for SCD, chronic manifestations of the disease contribute to the morbidity later in life (Table 68–5). Thirty years ago, complications from SCD contributed to high mortality. It was estimated that approximately 50% of patients with SCD did not survive to reach adulthood.4 Since that time data suggest improvement in mortality rates for patients with SCD. The survival age for individuals with HbSS has increased to at least the fifth decade of life. Recent reports suggest 85% survival by 18 years of age.4 SCD is a chronic disease and cannot be cured, except in some patients with transplant.
Patient Care and Monitoring
1. Assess the patient’s symptoms to determine whether the patient should be evaluated by a physician and/or receive immediate care. Determine the type of symptoms, onset of symptoms, frequency and exacerbating factors. Does the patient have evidence of SCD-related complications?
2. Review any available diagnostic data to determine the severity and status of the patient’s SCD. When was the patient last hospitalized for SCD complications?
3. Obtain a thorough history of prescription, nonprescription and natural drug product use. For pain control, determine which treatments have been helpful to the patient in the past. Is the patient currently taking any medications on a chronic basis?
4. Educate the patient on lifestyle modifications that may lessen complications. These include maintaining adequate hydration status, avoiding extreme temperature changes, dressing appropriately for hot or cold weather, and avoiding physical exertion, smoking, and excessive alcohol intake.
5. Is the patient up to date on immunizations? Have they received their annual influenza vaccine? If not, why?
6. Is the patient taking appropriate doses of their pain medication to achieve effect? If not, why?
7. Develop a plan to assess the effectiveness of pain medications.
8. Determine if the patient is a candidate for hydroxyurea therapy.
9. Assess improvement in quality of life measures, such as physical, psychological, and social functioning and well-being.
10. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
11. Stress the importance of adherence with the therapeutic regimen, including lifestyle modifications. Recommend a therapeutic regimen that is easy for the patient/parent to accomplish.
12. Provide patient education on disease state, lifestyle modifications, and drug therapy:
• Possible complications of SCD, both long- and short-term.
• When to take their medications.
• What potential adverse effects may occur?
• Which drugs may interact with their medication therapy
• Warning signs to report to the physician (increased or new pain, sudden headache, bleeding or bruising, fever, loss of energy, loss of appetite)
Starting with birth, SCD patients should have regularly scheduled health assessments and interventions when necessary. Obtain a urine analysis, complete blood count, liver function tests, ferritin or serum iron level and total iron binding capacity, blood urea nitrogen (BUN), and creatinine on at least a yearly basis and more often for children younger than 5 years of age to monitor for complications. All SCD patients should have regular screening of their hearing and vision.
All patients and parents of children with SCD should have a plan for what to do in the event of symptoms of infection or pain. Obtain a medication history when patients are admitted to the hospital. Assess compliance with prophylactic penicillin and childhood immunization schedules in all pediatric SCD patients.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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