Inpatient Management of Sickle Cell Disease

I n p a t i e n t Ma n a g e m e n t o f Si c k l e Cell Disease Susan Hunt,

MD

a,b,

*, Joseph Alisky,

c MD, PhD

KEYWORDS  Sickle cell disease  Inpatient management  Vasoocclusive crisis  Hemoglobinopathy  Acute chest syndrome  Bone marrow transplantation

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Sickle cell disease is a group of hereditary hemoglobinopathies characterized by the presence of hemoglobin S, which is caused by a valine to glutamate substitution in the gene coding for the beta globin chain. 2. The most common reason for hospitalization of patients with sickle cell disease is vasoocclusive crisis, which results from the blockage of small blood vessels by sickled cells, with pain resulting from localized ischemia, vascular endothelial damage, and inflammation. 3. Intravenous hydration and pain control with nonsteroidal antiinflammatory drugs and narcotics are the mainstays of inpatient therapy for vasoocclusive crisis. 4. Complete blood count, reticulocyte count, and basic metabolic panel should be routinely ordered on admission for vasoocclusive crisis, with urine analysis, chest radiograph, and cultures as needed for urinary, respiratory, or infectious symptoms. 5. Blood transfusions do not help with the alleviation of pain crises but are warranted in patients having end-organ damage or symptomatic anemia; the posttransfusion goal should not exceed hemoglobin 10% or hematocrit 30 because this can increase viscosity and worsen sickling. 6. Exchange transfusion (removing a few units of native blood and replacing them with donor blood) is helpful for patients with severe end-organ damage, such as acute chest, stroke, or multisystem organ failure. CONTINUED

a

Department of Medicine, University of Washington Medical Center, Box 356429, Seattle, WA 98195, USA; b Seattle Children’s Hospital, 4800 Sand Point Way NE, Seattle, WA 98105, USA; c Hospital Medicine Group, Division of General Internal Medicine, University of Colorado Denver, Campus Box F782, Leprino Building Room 936, 12401 East 17th Avenue, Aurora, CO 80045, USA * Corresponding author. Department of Medicine, University of Washington Medical Center, Box 356429, Seattle, WA 98195. E-mail address: [email protected] Hosp Med Clin 2 (2013) e247–e262 http://dx.doi.org/10.1016/j.ehmc.2012.11.001 2211-5943/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

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CONTINUED

7. Clinically significant complications seen in inpatients with sickle cell disease include acute chest syndrome, acute stroke, leg ulcers, osteomyelitis, aplastic crisis, and hyperhemolysis. 8. Perioperative management of patients with sickle cell disease includes adequate hydration and aggressive DVT prophylaxis; preoperative transfusions are not routinely recommended but may be considered on a case-by-case basis. Common operations include cholecystectomy, tonsillectomy, and splenectomy. 9. New modalities include bone marrow transplantation in patients who suffer strokes; life-threatening complications of vasoocclusive crisis, such as large pulmonary emboli; or severely compromised quality of life.

DEFINITIONS

1. What is the definition of sickle cell disease? Sickle cell disease (SCD) is a group of hereditary hemoglobinopathies characterized by the presence of hemoglobin S (Hgb S) caused by a single amino acid substitution in the beta globin chain. The substitution confers reduced solubility, particularly in the deoxygenated state, resulting in polymerization and deformation of the red blood cell (RBC) (sickling). SCD includes homozygous patients with hemoglobin (Hgb) SS; and compound heterozyges with other hemoglobinopathies, including Hg SC and Hgb Sb thalassemia, which tend to have more mild disease manifestations. 2. What is a vasoocclusive crisis? Vasoocclusive crisis (VOC), also termed sickle cell pain crisis, results from the blockage of small blood vessels by sickled cells, with pain resulting from localized ischemia. Additional contributing factors likely include associated vascular endothelial damage and inflammation. Over time, recurrent VOC with intermittent ischemia can result in chronic end-organ damage, which is also characteristic of SCD. EPIDEMIOLOGY OF INPATIENT TREATMENT OF SCD4

1. What is the prevalence and life expectancy of SCD? With advances in medical care, including early identification by newborn screening and use of prophylactic penicillin, pneumococcal vaccination and hydroxyurea, life expectancy in SCD has improved since the 1980s; 93% to 99% of patients are now expected to live beyond 20 years of age.1 Life expectancy varies based on type, with the previously noted median age of death in Hgb SS disease of mid-40s and near-normal ranges in Hgb SCD; these numbers predate the medical advances noted earlier and likely now represent underestimates.2 Adjusting for early mortality, US prevalence of SCD is estimated to be around 70 000 to 100 000 persons.3,4 2. How often are patients with SCD admitted to the hospital? Emergency department (ED) visits and hospital admission are significantly more common in patients with SCD compared with age- and race-matched populations, with the risk of hospitalization increasing as much as 7 to 30 times baseline.5 The

Inpatient Management of Sickle Cell Disease

average number of inpatient admissions varies between 2 to 3 per year, although such averages tend to be skewed by a small proportion of high utilizers.5–7 For example, a population analysis in Tennessee found that over the course of a year, 60% to 70% of patients with SCD had no admissions, 15% to 20% had a single admission, and 12% to 25% had 2 or more admissions.5 High utilizers, typically defined as patients with greater than 4 to 5 admissions per year, usually compose 20% of the SCD population in various cohort analyses but account for more than 50% of health care use.5–7 High utilizers also have increased and early mortality compared with the overall SCD population.8–10 The admission rates for SCD are higher than for either congestive heart failure or asthma, with correlating increased medical costs per patient because 80% of costs related to SCD care are associated with inpatient admissions.11,12 3. Why are patients with SCD admitted to the hospital? Most admissions in patients with SCD are for VOC, ranging from 77% to 97% of all admissions.6,10 Of these admissions, 66% to 97% originate from an ED visit, with nearly 33% of all ED presentations resulting in admission.6,7 The average length of stay for VOC ranges from 4 to 7 days, whereas less common admissions for surgical issues tend to be longer.6,10,11 High utilizers are more likely to have longer inpatient stays and comorbidities, such as acute chest syndrome, pneumonia, aseptic necrosis, and sepsis; these comorbidities were also associated with readmission in all patients.10,13

VOC Presentation and Evaluation

1. What is the typical presentation of VOC? VOC consists of acute onset of pain without an alternative source. Episodes are typically unpredictable and pain intensity is variable. Pain character can be either somatic, such as muscle, ligament, or joint pain, or visceral, with more vague symptoms, such as referred pain, nausea, and vomiting.14 2. What should be included in initial evaluation of VOC? There are no established physiologic or laboratory markers for rating pain in VOC; the gold standard remains patient report.14 Pain should be evaluated and documented using a validated rating system; examples include the Brief Pain Inventory, the visual analog scale, or the numeric rating scale. Although VOC is usually unpredictable, certain events can contribute to onset, including dehydration (often in the setting of other illnesses), acidosis, hypoxia, infection, or stress. The initial history should cover signs of infection, including fever, and localizing symptoms, such as rhinorrhea, sore throat, chest pain, cough, shortness of breath, abdominal pain, or dysuria. Vitals should assess for fever, hypoxia, or tachycardia and the examination should include a full respiratory examination for signs of infection; a cardiac examination, particularly for flow murmurs; and a joint examination for swelling or tenderness. 3. What studies should be sent to evaluate patients with VOC? The workup should center on potential triggers for crisis, as noted earlier, and ruling out significant complications that may accompany crisis. Recommended admission studies are noted in Table 1.

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Table 1 Recommended studies in VOC Study

Evaluates for

Caveats

Complete blood count

Acutely worsening anemia Leukocytosis (in infection)

Compare with baseline (when possible)

Reticulocyte count

Aplastic anemia

LDH, bilirubin

Hemolysis

If worsening anemia

Basic metabolic panel

Dehydration

To guide fluid resuscitation

Urinalysis

Infection

If urinary symptoms present

Chest radiograph

Infection Acute chest syndrome

If respiratory symptoms or chest pain

Cultures (blood, urine)

Infection

If fever present, particularly if indwelling line present

Abbreviation: LDH, lactate dehydrogenase.

4. When should patients with VOC be admitted to the hospital? Most pain crises are managed on an outpatient basis, particularly in sickle cell centers with pioneering day infusion centers. Patients who present to the ED, however, have often exhausted home options for pain control and are, therefore, likely to require admission. The decision to admit should be based on medication needs for adequate pain relief, such as the use of multiple intravenous (IV) narcotic doses in the ED. 5. What chronic medications should be addressed on admission and discharge? The use of hydroxyurea (HU) treatment of adults with SCD can significantly reduce the frequency of pain crises, including ED use and admission.15 Unless patients are in aplastic crisis or unable to take oral medications, HU should be continued during an admission for VOC. Iron chelation is an important part of managing iron overload in patients with SCD requiring frequent transfusion, a population with high inpatient usage. Oral chelators, such as deferasirox (Exjade), have improved morbidity and mortality in such patients by improving compliance with chelation therapy because of the ease of use over IV chelators. Oral chelators should be continued during VOC unless patients are unable to take oral medications. Treatment

1. What opioid pain management options are available for inpatients with VOC? There have been few randomized trials to guide treatment, most of which are underpowered and do not address opiate choice.16 The guidelines for management are, therefore, based on expert opinion and often extrapolated from treatment of other pain syndromes; the most comprehensive resource presently is the guideline published by the American Pain Society.14 For VOC severe enough to warrant hospitalization, opioid medications should be included in first-line treatment and are typically administered intravenously. When possible, the selection of opioid should be tailored to patients’ prior history, including a review of chronic pain medications (if any), breakthrough medications used since the onset of the current pain episode, and the usual dosing during a crisis. When such guides for treatment are not available, the initiation of opioid treatment with morphine

Inpatient Management of Sickle Cell Disease

or hydromorphone is preferred for inpatients because both medications are available in IV and oral formulations, allowing ease of transition to oral dosing as pain improves. Meperidine is not recommended for the treatment of VOC pain because of the potential toxic neurologic side effects of its metabolite, normeperidine. In cases when allergies or intolerance to other opioids limit choices, meperidine should be used for no more than 48 hours and should not exceed doses of 600 mg in a 24-hour period. Table 2 gives initial starting doses for patients with SCD experiencing severe pain; for those with moderate pain, starting with 50% of the noted doses is appropriate. In patients with SCD, opioid treatment should follow 5 principles:     

Titrate to relief Maintain relief with around-the-clock dosing Use rescue dosing for exacerbations Reassess pain relief with each dose Change medications based on tolerance

Following the initial loading dose, opioids should be given every 30 to 60 minutes with half of the initial dose to titrate to adequate analgesia. Relief should then be maintained with scheduled dosing based on the total dose required to achieve initial relief. Maintenance dosing is often provided with long-acting oral or transdermal preparations. Rescue dosing using the same opioid as the around-theclock medication should be calculated for breakthrough pain (Table 3). Pain relief should be reassessed and documented at the peak effectiveness of the opioid, typically at 60 minutes for oral and 30 minutes for parenteral administration. When relief is inadequate despite high doses or titration is limited by side effects, changing opioids can be attempted; calculation of the total daily dose (TDD) should be completed and the new opioid started at half of the equianalgesic dose to reduce the risk of overdosing caused by incomplete cross-tolerance between opiates. 2. When should patient-controlled analgesia be used in treating VOC? Patient-controlled analgesia (PCA) is an additional option that combines both maintenance dosing (as continuous infusion) and rescue (bolus) dosing and has been shown to improve pain relief in acute postoperative pain. PCA can be used in institutions where physicians are trained in their use; some institutions may have special pain services that manage PCA dosing. A preliminary study comparing high continuous/ low-demand dosing with low continuous/high-demand dosing found that adults in

Table 2 Equianalgesica starting doses for intermittent opioid administration in opioid-naive adults 50 kg or more with severe pain

a

Opioid

Oral

Parenteral

Dosing Ratio (Oral/Parenteral)

Morphine

10–30 mg q3–4h

5–10 mg q2–4h

3:1

Hydromorphone

7.5 mg q3–4h

1.5 mg q3–4h

7.5:1.5

Oxycodone

10 mg q4–6h

n/a

n/a

Note: Published tables vary in the suggested dosages that are equianalgesic to morphine. Clinical response should be evaluated in each patient. There may not be complete cross-tolerance among drugs. Abbreviation: n/a, not applicable.

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Table 3 Sample calculations for opioid dosing Type of Dose

Calculation

Example

Result

Rescue dosing: Oral

0.1–0.15  TDD opioid

Controlled-release morphine 50 mg po BID 5 morphine100 mg daily TDD  0.1–0.15

Immediate release morphine 10–15 mg po q1–2h prn

Rescue dosing: Parenteral/PCA

0.25–0.5  hourly opioid infusion dose

Morphine infusion 10 mg/h  0.25–0.5

Morphine 2.5–5.0 mg IV q30 min prn or PCA demand

Changing opioids

0.5  (equianalgesic prior dose)

0.5  (morphine 20 mg IV q2h  hydromorphone IV 1.5 mg/morphine IV 10 mg)

Hydromorphone 1.5 mg IV q2h

Abbreviations: PCA, patient-controlled analgesia; TDD, total daily dose.

the latter group used larger cumulative opioid doses to achieve pain relief; however, the sample size was too small to show significance.17 Dosing should, therefore, be based on extrapolating TDD based on prior relief dosing and current usage, with no more than 50% of TDD as the initial continuous infusion to maintain safety. 3. What ancillary pain treatments are evidence based for VOC? Nonsteroidal antiinflammatory drugs (NSAIDs) are hypothesized to improve pain in VOC because of their analgesic and antiinflammatory effects. NSAIDs have been studied in several small randomized trials; parenteral NSAIDs (ketorolac) showed improved pain control when given as a continuous infusion in one study, whereas single-dose or oral NSAIDs seemed less effective; however, the latter studies had follow-up periods of hours and are, therefore, less likely to apply to an extended inpatient stay.16 Acetaminophen has not been studied independently in randomized trials but is often used given the low-risk profile in most patients. Steroids have been studied in small trials showing decreased length of analgesic medication use and length of stay; however, no pain assessments were included in outcomes and the sample sizes were small.16 Although some antidepressants and antiepileptics have been used as ancillary treatments in other chronic pain conditions, no randomized studies of these treatments have been completed in SCD for either acute or chronic pain. Therefore, in patients without contraindications, guidelines indicate that scheduled NSAIDs are the first-line treatment for outpatient treatment of mild to moderate pain; both NSAIDs and acetaminophen are recommended as adjuncts to opioid therapy in moderate to severe pain, such as during inpatient stay. No specific recommendations for steroids are made in routine VOC. 4. What principles guide non–pain-based therapies for VOC? The pathophysiology of SCD complications is related to blood viscosity; increased viscosity limits both blood flow and oxygen transport causing VOC and end-organ damage. Deoxygenated sickle cell blood has higher viscosity than normal blood at the same hemoglobin level; this increased viscosity can promote sickling, setting up

Inpatient Management of Sickle Cell Disease

a vicious cycle of progressive disease.18 Many of the ancillary treatments for VOC and other sickle cell complications are aimed at decreasing this viscosity by  Preventing deoxygenation (oxygen therapy, incentive spirometry)  Diluting RBCs (aggressive hydration)  Reducing the concentration of sickle Hgb (transfusion) 5. Do supplemental oxygen and incentive spirometry improve patients with VOC? Given the role of deoxygenation in sickling, the administration of oxygen has been a standard part of initial care in patients with SCD admitted with VOC. In the absence of hypoxia, however, small studies of oxygen administration during pain crisis did not find any difference in pain, opioid use, or length of stay compared with placebo.19,20 The use of routine oxygen supplementation is not recommended unless hypoxia or pulmonary symptoms are present. Incentive spirometry has been shown to decrease the risk of pulmonary complications, such as atelectasis and infiltrates in inpatients with SCD-associated chest pain; this low-cost, low-risk intervention should be considered.21 6. Do supplemental IV fluids improve patients with VOC? Adequate hydration during VOC is important to reduce blood viscosity and prevent further sickling. Patients with SCD are prone to dehydration caused by decreased fluid intake during acute illness, insensible losses, and decreased ability to concentrate urine caused by insidious damage to renal tubules. Unfortunately, randomized trials to guide hydration are lacking22; therefore, guidelines are based on expert consensus. If clinical dehydration is suspected, volume expansion with isotonic fluids is recommended; however, these should be transitioned to hypotonic fluids (such as 0.45% normal saline) when euvolemia is reached to avoid volume overload. 7. When should patients with SCD be transfused? RBC transfusion in patients with SCD serves several purposes23:  Increases oxygen carrying capacity (through increased Hgb level)  Decreases blood viscosity by decreasing concentration of sickle Hgb  Suppresses synthesis of sickle RBCs Blood transfusions carry inherent risks, including acute complications, such as volume overload and infections, and chronic complications (if repeated transfusions are required), such as alloimmunization and iron overload syndrome. To minimize complications, several general guidelines are suggested when considering transfusion in patients with SCD:  Asymptomatic anemia with an appropriate reticulocyte count does not warrant transfusion.  Transfusion does not reduce acute pain in uncomplicated VOC and should not be used in that setting.  Patients with SCD should undergo extended RBC antigen matching to include C, E, and K antigens to reduce alloimmunization.24  The transfusion goal should not exceed Hgb 10% (hematocrit 30) to reduce the risk of viscosity-related complications.18,23 Although chronic transfusions may be used in the outpatient setting as prophylaxis, particularly in children, most inpatient transfusions are therapeutic. Therapeutic

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transfusions typically address one of 2 general problems: severe anemia plus complicating factors or severe complications of VOC (Table 4). 8. When should exchange transfusion be considered instead of simple transfusion? Exchange transfusion involves removal of patients’ sickle RBCs and replacement with exogenous RBCs with the goal of decreasing Hgb S concentration to less than 30%.18 Compared with simple transfusion, exchange transfusion requires a greater number of transfused packed red blood cell (PRBC) units; benefits include iron neutrality (in complete exchange) and decreased risk of volume overload. Preparation for exchange transfusion should include appropriate access (dual large-bore peripheral access, a temporary pheresis catheter, or rarely a specialized dual-lumen vortex port), pretransfusion hydration (either oral or IV if patients are required to have nothing by mouth), and holding preprocedure blood pressure medications.18 Although studies of exchange versus simple transfusion are mostly observational, expert consensus indicates that exchange should be considered in the following situations: First-line therapy  Acute stroke in children  Acute chest syndrome if uncontrolled hypoxia, ventilator therapy required, or multilobar disease  Acute multiorgan system failure whereby Hgb is too high for simple transfusion Second-line therapy  Acute chest syndrome or multiorgan system failure refractory to simple transfusion  Preoperative transfusion undergoing major surgery Controversial/not recommended  Priapism Table 4 Indications for acute therapeutic transfusion Category

Indication

Cause

Severe anemia plus

Acute symptomatic anemia

Blood loss Hemolysis Suppressed RBC synthesis Parvovirus B19 Splenic or hepatic

Aplastic crisis Acute sequestration Severe complications of VOC

Acute chest syndrome

Acute multiorgan system failure

Pulmonary infection Fat embolism Pulmonary infarction Presumed infarction affecting kidneys, liver, or lungs

Acute strokea a

Evidence extrapolated from children. Data from Swerdlow PS. Red cell exchange in sickle cell disease. Hematology Am Soc Hematol Educ Program 2006;48–53; and Lottenberg R, Hassell KL. An evidence-based approach to the treatment of adults with sickle cell disease. Hematology Am Soc Hematol Educ Program 2005;58–65.

Inpatient Management of Sickle Cell Disease

INPATIENT COMPLICATIONS OF SCD

1. What are some clinically important complications of SCD? Acute Chest Syndrome

The most common inpatient complication seen by hospitalists is acute chest syndrome, which is defined as a new infiltrate on chest radiograph in the setting of VOC and in combination with one of the following: new chest pain, cough, wheezing, tachypnea, or fever.25–27 Management depends on severity; the most critical task is to monitor respiratory status and transfer patients to an intensive care unit if respiratory failure seems imminent. Supplemental oxygen, generous IV fluids, and adequate narcotics should be given; broad-spectrum antibiotics against common pulmonary pathogens should be started even in the absence of sputum or blood culture identification of a specific bacterial infection.25–27 When infection is the source, Chlamydia pneumoniae and Mycoplasma pneumoniae are common; empiric antibiotic coverage should include these atypical pathogens.28 Occasionally, fat emboli or pulmonary venous thromboemboli may be the cause of acute chest syndrome; the latter is treated with anticoagulation, whereas the former just warrants supportive care, with special attention to oxygenation. Incentive spirometry and use of bronchodilators like albuterol should be encouraged for all patients with acute chest syndrome. Systemic corticosteroids are controversial; clinical trials show that they can speed hospital discharge in patients with acute chest syndrome but then are associated with an increased rate of relapse and rehospitalization.25–27 Administering inhaled nitric oxide can be useful for severe cases of acute chest syndrome.29–32 Nitric oxide was originally approved for the treatment of primary pulmonary hypertension, and patients with acute chest syndrome may already have either acute or chronic pulmonary hypertension as a chronic complication of SCD. Individual case histories show that patients having acute chest syndrome with pulmonary infarction or pain crises complicated by stroke get quicker resolution of pulmonary symptoms with inhaled nitric oxide. Note, however, that a randomized placebo-controlled trial of inhaled nitric oxide for patients having regular pain crises did not show any benefit.33 Emergent exchange transfusions may help stabilize patients; in the worst cases, mechanical ventilation should be provided until respiratory status improves. If patients are declining even on a ventilator with exchange transfusions, extracorporeal membrane oxygenation can be done in some specialized tertiary care centers.34 Acute Stroke

Acute stroke is less common than chest syndrome. Strokes for patients with SCD can be either hemorrhagic or ischemic.35 Patients with hemorrhagic strokes should be immediately transferred to a neurology or neurosurgery intensive care unit, with either primary management or consultation by neurosurgeons and neurologists. For ischemic stroke, treatment is generally the same as would be if patients did not have SCD.35 Outcomes are generally better in a dedicated stroke unit, and the same 3-hour window of opportunity for giving tissue plasminogen activator (TPA) applies. SCD and active VOC are not contraindications to TPA36; however, a high number of patients with SCD have prior unrecognized, silent strokes (up to 25% of adults)37 that would be a relative contraindication to TPA if they occurred within 6 months of the overt cerebrovascular accident. Imaging of the brain with magnetic resonance imaging (MRI) is superior to computed tomography scans for determining probable age of any old strokes; use of imaging should be determined by the speed

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with which such studies could be obtained and the risk/benefit analysis on a case-bycase basis. As with acute chest syndrome, exchange transfusions are an important part of therapy for stroke in patients with SCD.38 Simple transfusions should usually be avoided in this situation because this can worsen the problem of relative hypervolemia caused by the increased viscosity of sickle cell erythrocytes. Inhaled nitric oxide may also be used in a critical care setting for patients with SCD having acute stroke.39,40 Leg Ulcers

Leg ulcers from arterial insufficiency are sometimes seen in patients with SCD. Superinfection, increased blood viscosity, decreased oxygen delivery, vasoocclusion, and venous incompetence all facilitate the development of ulcers in areas of the leg with less subcutaneous fat and collateral circulation, such as the ankles, anterior tibial area, Achilles tendon, and the dorsum of the foot.41 Treatment is based on severity, which is staged similar to decubitus ulcers (stage 1, intact skin; stage 2, partialthickness skin loss; stage 3, full-thickness skin loss; stage 4, subcutaneous tissue destruction).42 Local wound care is sufficient for stage 1, with revascularization, hyperbaric oxygen, systemic antibiotics, and plastic surgery needed for stage 4. Patients with a history of acute chest syndrome or cerebrovascular accident or sustained priapism from SCD are more prone to leg ulcers.41,42 Osteomyelitis

Osteomyelitis (OM) is very common in SCD because of the decreased immune surveillance from asplenia and bone infarction from VOC, which creates a milieu favorable for bacterial growth.43 The most common pathogens are various Salmonella species; Staphylococcus aureus; and gram-negative enteric bacteria, such as Escherichia coli and Pseudomonas aeroguinosa.43 Differentiating OM from VOC based on clinical examination alone can be challenging because both conditions produce bone pain and malaise. If OM is suspected, additional studies, including preantibiotic blood cultures, plain radiographs, and MRI of painful bones, and bone scans are almost always needed to obtain a proper diagnosis.43 A recent systematic review could not identify any particular empiric antibiotic regimen as more effective for OM in SCD,44 so the choice of antibiotics should be based on sensitivity of pathogens isolated, when possible, or using patient, community, or hospital-specific resistance patterns. Severe Anemia: Specialized Situations

Rarely, very sick inpatients with SCD may manifest profound anemia as part of aplastic or hypoplastic crisis.45 In aplastic crisis, patients with SCD are not able to make new RBCs to replace those lost to hemolysis; bone marrow biopsy shows a profound depletion of erythroblastic progenitor cells. The most common cause is acute infection with parvovirus B19, a ubiquitous DNA virus that causes subclinical infection in individuals without SCD or other hemoglobinopathies.45 The parvovirus B19 has preferential tropism for erythroid precursor cells resulting in temporary cessation of hematopoiesis while the immune system clears the virus. Treatment is supportive, with simple transfusions or exchange transfusions as needed. Parvovirus B19 is transmitted via respiratory droplets but may also be spread via blood transfusions and, hence, put transfusion-dependent patients with SCD at particular risk.45 If parvovirus is proven by polymerase chain reaction detection of viral DNA, IV immunoglobulin can be helpful in hastening recovery.46 Other infectious pathogens, such as mycoplasma, may also trigger aplastic crisis.47

Inpatient Management of Sickle Cell Disease

Another severe but rare inpatient problem is hyperhemolysis syndrome whereby blood transfusions trigger accelerated and aggressive hemolytic reaction. The hyperhemolysis syndrome may overlap with aplastic crisis, but preformed antibodies of various types are usually the culprit. Treatment is again supportive, with exchange transfusions and IV immunoglobulin; if there is no active infection, corticosteroids can also be given.48 2. What are the most common causes of mortality in SCD? Acute chest syndrome tops the list of all-cause mortality in most series of adult inpatients with SCD, followed by stroke, myocardial infarction, cardiac arrhythmias, and sepsis.2,49 Sepsis can be a special problem in patients with functional asplenia. Pulmonary hypertension is a significant cause of mortality and can present either as a chronic complication or as an acute, unexpected decompensation in hospitalized patients.50,51 3. What are preoperative considerations in patients with SCD? Certain operations are more commonly needed in patients with SCD, such as cholecystectomy, splenectomy, and tonsillectomy with adenoidectomy; hospitalists may be consulted to help with perioperative management for these and other types of surgeries.52 A common concern is whether patients with SCD undergoing surgery should have preventative blood transfusions. Although transfusion is commonly performed, studies do not indicate any decreased incidence of complications in patients receiving prophylactic exchange or simple transfusions before surgery, unless patients are having symptomatic anemia.53,54 Adequate IV hydration is important to reduce the risk of triggering a VOC when patients are convalescing and oral intake is low but should strive for euvolemia and transition to maintenance fluids when possible. Patients with SCD have a higher-than-average risk of deep venous thrombosis and pulmonary embolism,55 so aggressive prophylaxis with sequential compression stockings or low-molecular-weight heparin should be routine for all patients with SCD, particularly those immobilized after surgery. FUTURE DIRECTIONS

1. How is bone marrow transplantation used in the present and future treatment of SCD? It is possible to eliminate sickle cell anemia with an allogeneic bone marrow transplantation (BMT) from a donor with normal hemoglobin. The first successful BMT that cured SCD was done in 1984 in a child who also had acute lymphoblastic leukemia, opening the door to BMT as a specific treatment of SCD.56 Since that time, the use of BMT for SCD has been limited by graft-versus-host reaction and availability of donors; therefore, this risky procedure is usually reserved for children with SCD who have strokes or other severe vascular events rather than to prevent recurrent pain crises.57–59 However, there are also reports of adults with SCD who have had BMT as part of the treatment of cancer similar to the pioneer pediatric case in 198460–62; a small number of adults have undergone BMT specifically to cure SCD.63 Recently, less toxic myeloablative regimens have been developed that ablate only a part of the native bone marrow, thus improving patient tolerance for transplant.64 Furthermore, partial chimerism (having both donor and recipient hematopoietic stem cells) may be enough to

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significantly alter the natural history of SCD.65 However, it is important to emphasize that current BMT procedures carry a significant risk of mortality (5%–20% depending on the patient series).66,67 The target population should be adults at significant risk of death caused by complications of recurrent VOC (strokes and acute chest syndrome) or those whose quality of life is so severely reduced by recurrent VOC that the risk of mortality becomes acceptable. Stem cells for BMT come from 3 sources: donor bone marrow, stem cells isolated from peripheral blood, and umbilical cord blood from newborn infants.68 Harvesting bone marrow stem cells is painful for the donor. Marrow is aspirated from the iliac crest or sternum similar to a bone marrow biopsy. Stem cells for BMT can also be obtained from peripheral blood after giving trophic factors to stimulate proliferation of stem cells and then collecting the stem cells by apheresis. Stem cells from bone marrow take longer to engraft compared with those from peripheral blood, but the incidence of graft versus host is less. Umbilical cord blood may be the best option when available; it is painless to obtain, and it has been reported that the incidence of graftversus-host disease is much lower with cord blood stem cells compared with other sources of stem cells.64 All 3 of these sources have been used successfully for SCD. To build on this success, to make BMT for SCD more available, it will be necessary to increase the supply of stem cell donors. Within the United States, difficulty finding matched donors for African Americans who make up most of the patients with SCD is a significant problem; but there are public health campaigns to encourage African Americans to volunteer to be donors.69 Hospitalists can help these efforts by explaining to families and patients the role of BMT for the treatment SCD. In other parts of the world, including Nigeria,70 South Africa,71 and several European and Middle Eastern countries,72 there are also ongoing efforts to create expanded donor registries specifically for BMT that hospital physicians treating SCD can promote. To summarize, BMT has a niche for the management of patients with SCD at risk of dying or being totally disabled by VOC; the eligibility for BMT should increase in the years to come. For today, hospitalists should keep in mind the possibility of BMT in adult patients with recurrent hospitalizations and complications from SCD and, when appropriate, ask the patients and their hematologists whether there should be further consideration of this ultimate therapeutic option. 2. Will gene therapy be the ultimate cure for SCD? Gene therapy has already cured SCD in animal models and cultured human hematopoietic stem cells. The only real question is when this will be extended to actual patients. Gene therapy is defined as the therapeutic transfer of a transgene to a target organ or tissue for treatment of disease. Gene transfer is accomplished by means of vectors, either modified viruses or nonviral vectors, such as liposomes carrying DNA plasmids. Via gene therapy vectors, it is possible to restore wild-type Hgb with homologous recombination at the site of the glutamate to valine point mutation.73,74 It is also possible to insert transgenes to derepress production of fetal hemoglobin in mice,75 which is another way to surmount SCD, which is comparable to how the currently used drug hydroxyurea works. Gene therapy for SCD would ultimately involve a BMT of transduced stem cells; as a result, there would be no graft-versus-host disease because autologous cells would be used. A similar technique has been pioneered in children with severe combined immunodeficiency; however, out of the 10 children undergoing the gene therapy, 3 developed subsequent leukemic transformation from the retroviral-based vector used for gene transfer.76 One way around this may be focusing on derepression of fetal Hgb production because in this approach

Inpatient Management of Sickle Cell Disease

transgenes can be maintained episomally rather than requiring site-specific recombination at the Hgb gene itself on the chromosome, enabling the use of nonretroviral vectors such as those made by genetic modification of adeno-associated viruses. Efficiency and permanency of gene transfer also has to be improved, but eventually these technical problems will be solved. SUMMARY

Inpatient management of SCD requires a careful and systematic approach, taking a proactive approach to issues of pain control, hydration, oxygenation, infection, anticipated complications, and new research. REFERENCES

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