Sickle Cell Disease: A Review of State-of-the-Art Emergency Management and Outcome-Effective Therapy
Authors: Charles R. Stephens, MD, Department of Emergency Medicine, Howard University Hospital, Washington, DC; Robert Linton, MD, Howard University Hospital, Washington, DC; Karim Cole, MD, Assistant Professor of Emergency Medicine, Department of Emergency Medicine, Howard Uni- versity Hospital Program, Washington, DC.
Peer Reviewer: Steven M. Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, Sturgis Hospital, Sturgis, MI, and Allegan General Hospital, Allegan, MI.
Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the production of hemoglobin S. The spectrum of clinical disease includes sickle cell anemia, hemoglobin SC disease, sickle beta-thalassemia, and sickle O-thalassemia disease. With manifestations that range from mild, discomfort-making symptoms and arthralgia to life- and limb-threatening complications, this well-studied group of disorders is commonly encountered in patients accessing emergency departments in large urban centers.
As is well known, SCD afflicts people of African, Mediterranean, Eastern Indian, and Middle Eastern heritage. In the United States, this condition most often affects African Americans, about 8% of who carry the sickle cell gene.1 From a clinical perspective, sickle cell anemia (SCA), or SS disease, occurs in approximately 0.3-1.3% of African-Americans.1 Other affected populations in the United States include Hispanics from the Caribbean, Central America, and parts of South America.1,2
SCD accounts for approximately 75,000 hospitalizations per year in the United States with an estimated average cost of $6,300 per hospitalization.3 The economic effect is greater than these statistics suggest, inasmuch as these numbers do not reflect extensive (and intensive) emergency department and non-hospital-based management efforts, which contribute substantially to the effect of this disease on patients and the health care system.
Given the widespread prevalence of SCD, it is essential that emergency physicians be familiar with current protocols, standards, and critical pathways that, in evidence-based trials, have been shown to improve patient outcomes and reduce hospitalizations. With these issues in clear focus, the purpose of this article is to provide an update on state-of-the-art management of acute complications and manifestations of SCD.
— The Editor
Clinical Principles and Overview
Emergency physicians must be clear about one thing: SCD is a very serious, debilitating condition and patients who have SCD have a shortened life expectancy. In hard numbers, the median age of death among persons with SS disease is 42 years for males and 48 years for females.4,5 In those with SCD, the median age of death is 60 years for males and 68 years for females.4 In the Cooperative Study of Sickle Cell Disease, approximately 85% of children and adolescents with SCA and 95% of patients with sickle cell hemoglobin C disease survived to 20 years of age. Among the patients younger than 20 years of age in that series, mortality peaked between 1 and 3 years of age; the primary cause of death was infection, most often associated with Streptococcus pneumoniae sepsis.
Risk factors associated with poor outcomes in SCD have been identified. In particular, low levels of fetal hemoglobin and an elevated, baseline white-cell count were associated with an increased risk of death.4 In this study, 78% of patients older than 20 years of age died during an acute painful episode or an episode of acute chest syndrome.4 Interestingly, 33% of these patients were considered relatively healthy (i.e., although they had no chronic organ failure, they died precipitously during a classic episode of painful crisis).4
In the same study, 18% of deaths occurred in chronically ill patients with clinically obvious organ-system failure (renal failure, CHF, or chronic debilitating cardiovascular disease (CVA). Acute, hemorrhagic stroke was also an important cause of death in relatively healthy patients. In general, adult patients with SCA, acute chest syndrome, renal failure, seizures, a baseline WBC greater than 15,000 cells per cubic millimeter, and a low level of fetal hemoglobin were associated with an increased risk of early death.4
Terminology and Syndrome Categorization
The hemoglobin molecule contains four heme units and four globulin chains. There are four different types of globin chains: alpha, beta, gamma, and delta. Of the four chains in a hemoglobin molecule, two are always alpha, and the other two are either beta (in hemoglobin A, the normal adult form), delta (in hemoglobin A2, a minor form), or gamma (in hemoglobin F, the fetal form).
SCD arises from a mutation in the beta globulin chain, specifically, a substitution of valine for the normal glutamic acid at position 6. Persons who are homozygous for the mutation (i.e., who inherit the abnormal gene from both parents) are said to have the "SS" genotype and they produce no normal hemoglobin Al. Instead, they produce mostly hemoglobin S and small amounts of hemoglobin F and hemoglobin A2.6 Hemoglobin C is a structural variant in which the normal glutamic acid at position 6 of the beta chain is replaced by lysine. Combined with the sickle cell gene, it is known as hemoglobin S/C disease. Similarly, the sickle mutation plus hemoglobin O Arab gives rise to hemoglobin S.O Arab.
Thalassemia is a mutation that impairs the synthesis of hemoglobin, but not its structure. Different forms of thalassemia affect alpha and beta globulin chains. As with SCD, persons can be heterozygous or homozygous for thalassemia. The symbol $+ indicates that production of the normal beta chain is decreased, whereas "$O" indicates that the normal beta chain is totally absent.
Of the forms of SCD, SCA is the most common, followed by hemoglobin S/C disease, sickle-$+ thalassemia, sickle-$0 thalassemia, and other combinations. In terms of severity, SCD is the most severe, followed by sickle-$0 thalassemia, hemoglobin S/C disease, and sickle-$+ thalassemia. However, this scheme does not always apply to the individual patient, and a patient with SCA may have mild disease, whereas an occasional patient with sickle-$+ thalassemia may have severe disease. (See Table 1.)
| Table 1. Sickle Cell Syndromes | ||||
| Type | Genotype | HCT | Retic | MCV |
| HbSS disease | Bs Bsaa/aa | 20-22% | 15% | 85-110 fl |
| Sickle-a-Thal | Bs Bsa-/a- | 26-28% | 6-12% | 75 |
| Sickle B0 | Bs B0aa/aa | 20-30% | 65 | |
| Sickle B+ | Bs B+aa/aa | > 30% | 65 | |
| HbSc disease | Bs Bcaa/aa | 20-30% | 80 | |
| Sickle Trait | Bs Baaa/aa | > 36% | > 82 | |
Sickle Cell Anemia. In sickle cell anemia (SCA), erythrocytes typically have a normal volume and hemoglobin concentration (i.e., they are normocytic and normochromic). The mean corpuscular volume is approximately 90 m3/cell (normal range, 86 to 98 m3/cell). The plasma hemoglobin concentration is low, between 7.0 and 8.0 g/dL (normal range, 14 to 18 g/dL for men, 12 to 16 g/dL for women). Both the white blood cell (WBC) count and the platelet count are increased due to increased marrow activity secondary to chronic hemolytic anemia and, in the case of platelets, to "auto-splenectomy," in which platelets are not stored in the spleen. The reticulocyte count is typically elevated.
Thalassemia. In SCA with homozygous alpha-thalassemia, persons have milder anemia, lower reticulocyte counts, low mean corpuscular volume, and high hemoglobin A2 levels. In hemoglobin S/C disease, patients typically have microcytic and hyperchromic red blood cell indices. In SCD with $0 thalassemia, patients typically have microcytosis, hypochromia, high hemoglobin A2 levels, and variable hemoglobin F values. In SCD with $+ thalassemia, the anemia is mild, usually with microcytosis and a hemoglobin level greater than 10 g/dL. (See Table 2.)
| Table 2. Sickle Cell Disease: Clinical Severity and Laboratory Characteristics | |||||||||
| Disease | Clinical severity | S (%) | F (%) | A2 (%) | A(%) | Hb G/dl | Retic (%) | MCV | RBC morphology |
| S | Usually marked | > 90 | < 10 | < 3.5 | 0 | 6-11 | 5-20 | 80 | Sickle cells, normochromia, anisocytosis, target cells, poikilocytosis, Howell-jolly bodies |
| S$° Thal | Marked to moderate | > 80 | < 20 | > 3.5 | 0 | 6-10 | 5-20 | < 80 | Sickle cells, hypochromia, microcytosis anisocytosis, poikilocytosis, target cells |
| S$+ Thal | mild to moderate | > 60 | < 20 | > 3.5 | 10-30 | 9-12 | 5-10 | < 75 | No sickle cells, hypochromia, microcytosis, anisocytosis, poikilocytosis, target cells |
| SC | Mild/moderate | 50 | < 5 | 0 | 10-15 | 5-10 | 75-95 | "fat" sickle cells, anisocytosis, poilkilocytosis, target cells | |
| S HPF-H | Asymptomatic | < 70 | > 30 | < 2.5 | 0 | 12-14 | 1-2 | 0 | No sickle cell, anisocytosis, poikilocytosis, target cells |
Clinical Pathophysiology. SCD results from a single nucleotide change in the sixth position of the beta-globulin chain. The normal glutamic acid at position 6 is replaced by valine-producing hemoglobin S. In persons who are homozygous for the disease, virtually all hemoglobin is hemoglobin S with small amount of hemoglobin F and hemoglobin A2.6 In person who are heterozygous for the disorder, half of the RBC contain hemoglobin S. In children, hemoglobin F is produced and levels fall to adult levels around 4-5 months. This accounts for the dearth of symptoms seen in this age group.
Vascular occlusion is the hallmark of SCD and is the basis for systemic, clinical manifestations. Hemoglobin S is abnormal in that it polymerizes when in the deoxygenated state. This causes the RBC to assume bizarre shapes, become less deformable, and predispose it to early destruction in the spleen and liver. Due to altered membrane characteristics and less deformability, sickled cells become trapped in the vasculature, causing occlusive symptoms, subsequent ischemia, and acidosis. A cascade that creates a vicious cycle causing more sickling. The presence of other hemoglobins, such as hemoglobin F and C, tend to ameliorate this sickling process and decrease the clinical severity of the disease.6 Early destruction of sickled red cells causes a chronic hemolytic anemia with elevated reticulocyte count.
Clinical Features
Hyperhemolytic Crisis. Hyperhemolytic crisis, as the name suggests, is a condition characterized by an increased rate of destruction of RBCs in patients with SCD. It is characterized by decreasing hemoglobin levels, increased reticulocyte count, indirect bilirubinemia, and elevated lactate dehydrogenase.6 The etiology of hyperhemolytic crises is variable, and many precipitants have been identified, including infections (i.e., Mycoplasma), delayed hemolytic transfusion reactions, and co-existent Glucose 6-phosphodisterase (PD) deficiency with oxidant stress. It may also occur during sickle cell painful crisis.
Aplastic Anemia. Aplastic anemia (AA) occurs when erythropoiesis is suppressed, usually in the setting of infection. Although Parvovirus B-19, which replicates exclusively in bone marrow red cell precursors, is the most commonly implicated infectious agent, this condition has also been linked to other infectious organisms, including pneumococci, salmonella, streptococci, and Epstein Barr virus.7,8 From a clinical perspective, aplastic crisis is characterized by fever, symptomatic anemia, reticulocytopenia (< 2%), serum IgM antibodies to parvovirus B-19, and the presence of B-19 DNA in serum or bone marrow cells.8
Aplastic crisis is more common in children than adults; previous exposure may confer subsequent immunity to the virus.8 Aplastic crisis terminates spontaneously after 5-10 days.9 Due to leuko-erythoblastosis that is present in the recovery phase, patients who present during the convalescent phase may be mistakenly thought to be in a hyperhemolytic crisis.9
Treatment of aplastic crisis is mainly supportive. Patients with hemoglobin SS and S beta 0 Thal disease usually require simple blood transfusion to ameliorate severe, symptomatic anemia.9 Hematological consultation should be obtained and patients should be placed in respiratory isolation, which is necessary to prevent exposure of pregnant females (i.e., nursing staff), patients with immunodeficiency disorders, and other patients with SCD.9 It is also important to stress that if the patient has parents or siblings who have SCD, these individuals also are at risk for developing aplastic crisis due to the communicability of the virus.10
Megaloblastic Anemia. Megaloblastic crisis in individuals with SCD can result from folate deficiency that is either due to lack of supplementation, poor dietary intake, or both. Folic acid therapy is required in SCD because this vitamin is readily depleted due to enhanced erythropoietic activity. Folate supplementation is extremely important, especially in patients taking dilantin, due to its propensity for causing meagaloblastic anemia. In addition to its therapeutic effects and its usefulness for prevention of megaloblastic anemia in SCD, folic acid also lowers high homocystiene levels, which have been linked to cardiovascular and cerebrovascular disease.6
Iron Deficiency Anemia. Iron deficiency anemia also may be encountered in patients with SCD. SCA disease is characterized by normochromic and normcytic morphology. Iron deficiency is heralded by hypochromic and microcytic morphology. Interestingly, iron deficiency has an ameliorating effect on sickling and may improve clinical manifestations of the anemia.6 However, if oxygen carrying capacity is reduced to a critically low level, these salutary effects are not observed.
Vaso-Occlusive (Painful) Crisis
Vaso-occlusive crisis is the hallmark of SCD and accounts for more than 90% of hospital admissions related to SCA.6 Vaso-occlusive crisis is believed to be the result of tissue ischemia and/or completed infarction associated with vascular occlusion precipitated by sickled erythrocytes. Current research indicates that vascular endothelium, humoral factors, and even white blood cells may contribute to the genesis of painful crisis.3,5
Clinically, conditions which may precipitate vaso-occlusive crisis include dehydration, infection, cold weather, physical and psychological stress, as well as other causes. (See Table 3.) Pain in the lower back, chest, abdomen, and extremities, usually without objective signs, is the typical clinical presentation. Most painful episodes can be treated effectively at home.11 The average length of painful episodes is 4-6 days but symptoms may persist for weeks.9 Less than 10% of patients with SCD have three or more painful episodes per year that require emergency department care. In this regard, it is important to note that three or more painful episodes per year has been identified as in indicator of severe disease and early mortality.12
| Table 3. Precipitants of Painful Crisis | |
| Hypoxia | Obstructive Snoring |
| Infection | Exposure to cold |
| Fever | Depression |
| Dehydration | Anxiety |
| Menstruation | Physical Exhaustion |
| Sleep Apnea | Unknown |
Unfortunately, there are no laboratory findings pathognomonic for painful crises. Hemoglobin levels are generally the same as they are at baseline. The WBC count, if elevated above baseline, is strongly suggestive of infection.
Management. Emergency department management of painful crisis should be aggressive and, in nearly all cases, should include administration of parenteral narcotics and a search for precipitating factors. As a rule, patients presenting to the emergency department have failed home therapy options, among them oral rehydration and oral, non-narcotic and/or narcotic analgesia. Because use of oxygen in non-hypoxic patients with SCD will result in erythroid hypoplasia and suppressed red cell production, oxygen administration, once considered mandatory, should only be used in patients who are documented to be hypoxic.9
Hydration. Hydration is a critical component in the treatment of painful crisis, inasmuch as dehydration usually is present due to increased insensible losses, reduced fluid intake, and hyposthenuria.9 For patients in mild to moderate painful crisis, oral hydration can be attempted as an initial measure, especially if sufficient personnel are available to encourage and monitor oral intake. However, in severe painful crisis, the patient is either unwilling or unable to take oral fluids and IV hydration is mandatory. Regardless of the route, the goal of hydration is to normalize electrolytes and maintain fluid balance. A good rule of thumb is to administer one and one-half times the patient’s daily requirements.9 Due to hyposthenuria, the use of D5, 0.25-0.50 normal saline (NS) is recommended as the initial fluid challenge. Judicious use of IV fluids will prevent overhydration and iatrogenic CHF.9
Analgesia. Morphine remains the drug of choice for painful crisis.9,13 The usual dose is 0.1-0.15 mg/kg every 3-4 hours IV, IM, or SQ with a single-dose maximum of 10 mg.13 The principal clinical advantages of morphine include a long, established safety record in other chronic pain syndromes, availability in various formulations (immediate release, controlled release, and [investigational] sustained release), and its hydrophilicity, which makes this analgesic suitable for administration by any route (oral, intramuscular, IV, SQ, rectal, intraspinal, etc.).13 The disadvantages of morphine include a relatively high incidence of pruritus, rash, nausea, and vomiting in patients with SCD.
Morphine 3-glucuronide and morphine-6-glucuronide are the two major metabolites of morphine. Morphine-6-glucuronide has a relatively long half-life (longer than that of morphine) and, therefore, it accumulates with repetitive dosing, especially in the presence of renal failure. In addition, morphine-6-glucuronide is a potent opioid analgesic and because of its long half-life, excessive sedation is possible.13 In addition, there have been reports of fatal pulmonary edema with the use of morphine in patients with SCA.13
Meperidine (Demerol) continues to be the most frequently used narcotic in the treatment of painful crisis of SCD in the United States and Great Britain despite some well-documented disadvantages.13 The desirable effects of meperidine includes its rapid onset of action, euphoric effect, and the low incidence of severe pruritus, nausea, and vomiting. However, the major disadvantage of meperidine is linked to one of its toxic metabolites, nor-meperidine. Whereas the half-life of meperidine is only three hours, that of nor-meperidine is 18 hours. Also, nor-meperidine is excreted by the kidneys and will accumulate in patients even with normal renal function. Nor-meperidine is a CNS excitotoxin that produces anxiety, tremor, myoclonus, and generalized seizures if it accumulates after repetitive dosing. The incidence of seizures in patients with SCD related to the use of meperidine varies between 1% and 12%. Caution and careful monitoring are required.13
Hydromorphone is a hydrogenated ketone of morphine and is a reasonable alternative to morphine and meperidine for treatment of acute painful crisis. The dose of hydromorphone is 0.01-0.02 mg/kg/dose IV or IM every 3-4 hours. Standard doses of 2-4 mg SQ are generally given in the adult patient. Hydrormorphone is metabolized by the liver and excreted renally. Consequently, it may also accumulate after repeated dosing.
Regardless of which analgesic is selected, a consistent approach to treating vaso-occlusive crisis must be employed. The drug should be given at regular intervals in conjunction with oral or IV hydration, and oxygen therapy, if indicated. A CBC with reticulocyte count should be obtained in all patients in which infection is suspected. A chest x-ray is indicated in patients who present with pulmonary symptoms or with a low pulse oximetry reading or abnormal PaO2 on an arterial blood gas. Evaluation of the effectiveness of analgesia should be objective using visual, analog, verbal, or numerical scales.13 If pain is not adequately controlled after 3-4 hours, inpatient therapy should be considered.
Acute Chest Syndrome
Acute pulmonary disease is the most common cause of death, and the second most common precipitant of hospitalization in adults with SCD.8,9 The term "acute chest syndrome" is used to describe acute pulmonary disease observed in SCD, with the understanding that distinguishing between infectious and non-infectious causes is often difficult.
The etiology of acute chest syndrome (ACS) in SCD is multi-factorial. Moreover, the presentation in children and adults is difficult to identify. The incidence of this complication is approximately 24.5 per 100 patient years in children with HbSS disease.9 A marked, seasonal variation is seen in the pediatric patient, with more cases encountered in winter than in summer.14 The most common bacterial etiology is Streptococcus pneumoniae, followed by H. influenzae.14 In one study, bacteremia was present in 78% of children with ACS associated with pneumococcus.14 Typically, children present with fever and cough. A fall in hemoglobin of 1-2 gm/dL is accompanied by relative thrombocytopenia and leukocytosis.14 Upper and/or middle lobe pulmonary infiltrates are the most common radiographic finding.14
In adult patients, there is a striking clinical association between ACS and painful crisis; in fact, 30% of patients who develop ACS initially present with extremity crisis.9,14,15 Etiologic agents in adults may include pneumococcus, streptococcus, mycoplasma, or chlamydia.15 Other possible causes are rib or sternal infarction, fat or bone marrow embolism, and pulmonary embolism.8,16,17 Adults usually present with severe chest pain, cough, and dyspnea.15 Other symptoms include productive cough and hemoptysis. Interestingly, most adult patients are afebrile. Hemoglobin levels are deceased by 1-2gm/dL; leukocytosis and relative thrombocytopenia are common. Lower lobe disease with pleural effusions is more common in adult patients.15
Management of patients with ACS depends on the severity of the disease. Initial management should consist of oxygen therapy to maintain the oxygen saturation (Pa02) above 92%. IV hydration and narcotics for pain are also mainstays of therapy. Inhaled beta-agonists are a safe and effective adjunct in patients who present with wheezing.8 Antibiotics should be used empirically to cover Streptococcus pneumoniae, H. influenzae, and atypical bacteria. Patients with a PaO2 greater than 60 mmHg could have a simple blood transfusion to raise the hemoglobin concentration to 10g/dL.8
Exchange blood transfusion is recommended for individuals who have severe hypoxia (Pa02 < 60).8 Patients who demonstrate pulmonary emboli should be anticoagulated with heparin or enoxaparin. Patients in respiratory failure will require intubation and mechanical ventilation. Hematology consultation should be obtained and exchange transfusions should be performed if indicated. Hydroxyurea and chronic hypertransfusion have been shown to reduce the incidence of recurrence of ACS.8
Acute Splenic Sequestration Crisis
Acute sequestration crisis is a well-recognized complication of SCD. It is classically defined as a fall in hemoglobin concentration of at least 2g/dL, an increased reticulocyte count, and an enlarging spleen.18 It occurs most commonly in children younger than 2 years of age and is unusual in adults with HbSS disease due to autosplenectomy. It is estimated that patients with SS disease have a 30% probability of having an acute splenic sequestration event by 5 years of age, with a potential mortality approaching 15% per event.18 Splenic sequestration can occur in older patients with HbS/C disease and S beta-Thal whose spleens either remain enlarged or retain the capability to enlarge.9
Splenic sequestration is caused by the accumulation of RBCs within the spleen. Clinical findings include sudden weakness, pallor of the lips and mucous membrane, tachycardia, tachypnea, and abdominal fullness. In severe sequestration crisis, the spleen can become so large that it fills the abdomen and pelvis.9 Laboratory studies reveal a decrease in hemoglobin level of at least 2 gm/dL and marked reticulocytosis. Relative or absolute thrombocytopenia is also a common finding. The fall in hemoglobin can be precipitous and reach 1.5 gm/dL within six hours.9
Management. Treatment of acute splenic sequestration crisis requires administration of high flow O2, restoration of intravascular volume with cystalloids, and/or volume expanders in anticipation of simple blood transfusion. It should be noted that the hemoglobin level rises approximately 3 g/dL more than would be expected from the number of units transfused as the spleen shrinks and expels trapped RBCs.8 The ultimate goal is to achieve post-transfusion Hgb levels of 6-8 g/dL. Urgent hematological consultation is recommended. All patients with acute splenic sequestration should be admitted to the hospital. Those who are hemodynamically unstable should be admitted to the intensive care unit.
Stroke and CNS Complications
Acute thrombotic or hemorrhagic stroke is a severe complication of SCD that affects both children and adults, occurring in approximately 11% of patients who have SCD by age 20.19 In the pediatric age group, it is most commonly encountered in the 6- to 10-year-old age group, whereas in adults, it is most common in the 20- to 29-year-old age group.9,10 In children younger than 10 years of age, cerebral infarction is more common, whereas in adults, hemorrhagic stroke is more common.19,20 Moreover, recurrent stroke is commonly hemorrhagic due to rupture of fragile, dilated collateral vessels from prior ischemic infarction.
In children, recurrence is higher in the third year post-event and many patients are on chronic exchange transfusion programs to reduce the level of Hb S to less than 30%, a maneuver that has been shown to reduce the incidence of recurrent stroke in well-controlled, prospective studies.21 Large vessel occlusion, especially affecting the anterior or middle cerebral artery, is found in 80% of cases involving children.9
From a diagnostic perspective, hemiplegia is the most common physical finding, but monoparesis, hemianesthesia, visual field deficits, aphonia, cranial nerve palsies, and altered mental status also can be seen as initial presenting signs and symptoms. The diagnosis is confirmed with a non-contrast CT scan. Acute intracerebral bleeding is readily detected with CT, although the scan may be negative in early ischemic stroke. Magnetic resonance imaging (MRI) is also an excellent modality if available on an urgent basis. The use of hyperosmolar contrast agent should only be undertaken with great caution in patients with SCD, since this therapy may promote sickling of RBCs.
Treatment must be aggressive. Increased intracranial pressure must be corrected but hyperventilation should be avoided. Seizures are common and anticonvulsant therapy should be initiated early. Exchange transfusion is indicated in the treatment of ischemic stroke but not for hemorrhagic stroke. Urgent hematologic and neurologic consultations are mandatory.
Gastrointestinal Manifestations
Hepatobiliary System. About two-thirds of people with SCD have hepatomegaly. Cholethiasis, consisting predominantly of calcium bilirubinate stones is present in 75% of patients, and is the result of chronic intravascular hemolysis. Acute hepatic sequestration can also occur and its presence is suggested by an enlarging liver, decreasing hemoglobin levels, and mildly elevated liver function test.6
Sickle cell intrahepatic cholestasis is a more severe form of hepatic crises which presents with right upper quadrant pain, increasing bilirubin levels, and elevated PT/PTT and liver function tests. This syndrome can be life threatening. Treatment consists of total blood exchange; whole blood is removed and replaced with packed RBCs and fresh frozen plasma (FFP). The goal of treatment is to reduce the HbS level to less than 30% and normalization of the PT/PTT.
Bone Complications
The bony skeleton is one of the primary organs affected by intravascular sickling. Blockage of the microcirculation causes infarction of bone marrow and adjacent bony structures.22 The cumulative effect of recurrent episodes of ischemia or infarction within the spongiosa of bone leads to prominent and characteristic radiographic changes of SCD.
Dactylitis (Hand Foot Syndrome). Hand foot syndrome may be the earliest manifestation of SCD.23,24 This clinical entity is seen primarily in children younger than 6 months of age, but can be encountered in children as old as 4 years old.24,25 These patients present with fever, pain, and swelling of the hands or feet. There may also be warmth or redness, a presentation that can mimic osteomyelitis.22 The leukocyte count and erythrocyte sedimentation rate (ESR) may be elevated above baseline, and radiographs may show periosteal elevation, which usually occurs several days after the episode.23
Symptoms of dactylitis are usually self-limited, and management of this syndrome is primarily symptomatic. Treatment includes analgesia, hydration, and warm compresses or baths.26 In light of the similar presentation of osteomyelitis, the clinician must maintain a high suspicion for osteomyelitis. High fever and/or extreme warmth or tenderness over the affected area should alert the clinician to the possibility of bone infection.27
Bone Infarction. Bone and bone marrow infarction are well-documented clinical consequences of chronic red cell sickling. During acute vaso-occlusive crisis, multiple marrow infarctions occur which can be demonstrated in bone marrow scintiscan using 99mTc sulfur colloid.28,34 Infarcts most commonly occur in long bones but have been reported in the spine, ribs, sternum, skull, and clavicle.22,23,26
The clinical presentation of patients with bone marrow infarction is similar to that described for dactylitis. Patients will complain of pain, tenderness, and, commonly, swelling over the involved area. Once again, any signs of sepsis, unusual sites of pain, persistent fever, or leukocytosis greater than baseline should warrant consideration of osteomyelitis. Bone marrow infarcts usually resolve in 1-2 weeks.23
Plain radiographs show a mottled, strand-like increase in density randomly distributed within the medullary region.35 In the early stages of infarction, plain radiographs are not helpful in distinguishing between bone infarction and osteomyelitis.23,26 Bone scans, including those using technetium or gallium, are neither highly specific or sensitive in differentiating the two entities.23,27,31 Blood cultures and culture of material aspirated from beneath the periosteum are essential for establishing a definitive diagnosis of osteomyelitis, in which salmonella remains the most common organism.22,31,32,37
Emergency department treatment of bone infarction is similar to that employed in painful crisis. Narcotic analgesics and hydration are required during the acute phase. NSAIDs can be helpful in providing pain relief by reducing the severity of the inflammatory response.23 No standard treatment is recognized, but the use of NSAIDs and physiotherapy may be of benefit in these patients.
Osteonecrosis (ON). This condition affects patients with all genotypes of SCD, but occurs most often in those with HbSS and alpha thalassemia.35 ON usually affects the articulating surfaces and heads of long bones. The overall prevalence of (ON) of the femoral head in SCD patients older than 5 years of age is about 10%. The prevalence of (ON) of the humeral head is approximately 5%.35
Patients typically present with complaints of pain or limitation of motion in the shoulder, hip, or other joints. Some patients describe worsening of their symptoms with movement of the joint (e.g., walking, climbing stairs). Pain also may worsen without movement. Intermittent or persistent groin or buttock pain is also, although less common, a presenting complaint of SCD patients affected by ON.36
In the early stages, radiographs appear normal.26 After several months, however, radiographs may show areas of increased density mixed with areas of increased lucency.22 Progression of radiographic findings include femoral head molding, segmental collapse, joint space narrowing, and complete joint degeneration.35
Presently, initial management of ON consists primarily of avoidance of weight bearing and judicious use of local heat and analgesics for up to six months. Osteotomy with rotation has been used with children with variable results. Core decompression of the femoral head, and also total hip or joint replacement must be considered for individuals beyond adolescence with incapacitating hip pain.26
Sickle Cell Nephropathy
Sickle cell nephropathy (SCN) is an important cause of morbidity and mortality in patients with SCD. There are well-characterized manifestations, risk factors, and prognostic features. As SCD patients reach the third and fourth decades of life, the clinical manifestations of SCN become more apparent.38,39
Pathophysiology. In addition to its many other effects, chronic sickling serves as the inciting event for renal microvascular damage.40,41 The arterial bed of the renal micro-vasculature has a low oxygen tension in a low pressure system. This promotes polymerization of HbS and subsequently, microvascular occlusion.38,42,43 Hemoglobin S polymerization is also facilitated via the low pH and hypertonicity of the renal medulla, which results in increased blood viscosity and interstitial edema. This cascade contributes to renal microvascular ischemia and infarction.44
Clinical Presentation. Hyposthenuria, which is defined as the inability to maximally concentrate the urine, is the first clinical manifestation of sickle cell induced renal failure.38 The initial response of the renal medullary system is increased glomerular filtration rate (GFR) and renal blood flow, which over time results in hyperfiltration-mediated glomerulosclerosis (GS). This leads to decreased GFR, progressive medullary ischemia, and ultimately end-stage renal disease (ESRD).38,44
Hematuria. Asymptomatic hematuria is one of the most common presentations of SCN, and one of the few potential manifestations in patients with sickle cell trait.44 These patients may present to the emergency department with microscopic-, or less commonly, gross-hematuria. Both microscopic and gross hematuria are usually self-limited, resulting in minimal blood loss. Bed rest and hydration may hasten the resolution of hematuria.47
End Stage Renal Disease (ESRD). The incidence of renal failure in SCD ranges from 5 to 18%.40,45 ESRD is a poor prognostic indicator in these patients with a mean four-year survival rate after diagnosis in one study.48 Persistent, increasing proteinuria is the harbinger of glomerular insufficiency and renal failure.38 It is a frequent finding in patients with SCD and has been shown to be present in up to 30% of patients during long-term follow-up.41 Nephrotic syndrome is found in 40% of patients with SCN, and may be a clinical marker for ESRD, evolving from the progression of glomerulosclerosis.41,46,48,49
In patients with SCN, although renal abnormalities begin at earlier ages, the development of ESRD occurs between the 3rd and 5th decades of life.39 Hypertension is a major risk factor for renal failure, and adequate management of this risk factor can delay the onset of ESRD in SCD patients.50 Angiotensin converting enzyme (ACE) inhibitors, such as enalapril, have been shown to achieve blood pressure control and lower urinary protein excretion.38
Dietary management with protein restriction is an important part of therapy for SCN. SCN patients who develop ESRD eventually require maintenance dialysis. Complication rates of SCD patients on dialysis are comparable to the dialysis population as a whole.38
Priapism. Priapism is characterized by persistent and painful failure of penile detumescence. In SCD, failure of detumescence may be secondary to venous outflow obstruction or to prolonged smooth muscle relaxation, either singly or in combination. During erection, there is a blockade of the alpha adrenergic stimulus resulting in vascular smooth muscle relaxation and increased blood flow. In the flaccid state, alpha-agonist stimulation contracts the corporal smooth muscle and cavernosal arteries resulting in detumescence.51-53
Most children with SCD will respond well to noninvasive medical therapy. More than 50% of adults, however, will respond poorly.54 During the emergency department evaluation of a SCD patient with priapism, information as to the time of onset and state of recurrence should be obtained. A complete urologic exam is warranted, with particular attention to the penile shaft and glans. A hard shaft, soft glans, and maintenance of the ability to urinate denotes minimal involvement of the corpus spongiosa. Urinary obstruction and glans engorgement are the hallmarks of secondary involvement of the corpus spongiosa which nearly always suggests cavernosa infarction. With repeated episodes, the cavernosa becomes fibrosed, leading to marked reduction in blood flow.51
Blood flow measurements should be obtained for SCD patients with priapism. These include technetium scintigraphy, infusion cavernosometry, color doppler cavernosometry, and MRI.55,56 Inpatient evaluation will require one of these techniques to evaluate blood flow and the degree of spongiosa involvement. Type of technique used will vary depending on the institution.
Standard, initial therapy of priapism in both adults and children begins with the treatment of pain and anxiety using hypotonic IV fluids and analgesics. Heat application increases blood flow and should increase venous return; however, it seems to benefit primarily those patients without infarction-mediated priapism.51 To date, definitive evidence for or against red cell transfusion is lacking, although this strategy continues to be used in the management of refractory priapism.
Controversy exists over the pharmacologic agent of choice for the treatment of priapism in SCD patients. Alpha agonists and beta agonists are two of the most commonly used agents. Phenylephrine and epinephrine are alpha agonists thought to promote vascular smooth muscle contraction of the helicline arteries of the cavernosa, thus increasing the flow of blood out of the cavernosa into the venous return. Alternately, vasodilators (beta agonists) such as terbutaline, have been used based on the theory that they induce vascular smooth muscle relaxation, favoring the entry of oxygenated arterial blood into the cavernosa, thereby washing out the damaged sickled red blood cells.57,58 The use of either agent is not supported by studies at the present time. The need for further investigation precludes a definitive pharmacologic therapy at this time.
Aspiration of the corpus cavernosa is a first-line surgical procedure that is used for sickle cell induced priapism. This procedure has not been shown to actually change the course of the episode, but on an acute basis it has the benefit of decreasing cavernous edema and subsequently reducing pain.51 Some of the other surgical procedures used include the glans-cavernosum (Winter) shunt and the cavernosaphenous shunts. Surgical intervention should be considered if there is no detumescence after 12-24 hours of conservative measures.38
Ophthalmologic Manifestations
Ophthalmologic complications of SCD are common and fall into the broad categories of nonproliferative and proliferative retinopathy. Nonproliferative sickle retinopathy includes vascular occlusions, retinal hemorrhages, retinoschisis cavities, iridescent spots, black sunburst, angioid streaks, and macular changes.9 These changes generally do not affect visual acuity. Proliferative sickle retinopathy is a common cause of visual loss in SCD and is characterized by retinal neovascularization. This is most common in patients with Hb SC disease in the second and third decades.9,60
The most important ocular emergency in patients with SCD is blood in the anterior chamber (hyphema), which usually occurs as a result of trauma or surgery. Due to low pH and P02 in the aqueous humor, red bloods cell containing Hb S tend to sickle and obstruct the flow of aqueous humor. Sharp rises in intraocular pressure may result. Unlike nonproliferative and proliferative retinopathy, hyphema, with its resultant rise in intraocular pressure, can also affect patients with sickle cell trait.60
Treatment of hyphema in the patient with SCD and sickle cell trait begins with a test of visual acuity and determination of intraocular pressures. If a globe rupture is suspected, intraocular pressure measurement should not be performed. The patient should be placed in the supine position with his or her head elevated to 30-45 degrees and a fox eye shield placed to prevent further trauma. Increased intraocular pressure (> 24 mmHg in a SCA or sickle cell trait) should be treated with timolol 0.5% ophthalmic bid. Pilocarpine 2% one drop every 15 minutes should also be used. If intraocular pressure (IOP) is still elevated, nepatazane 50mg po q8hr should be given. Acetazolamide should not be used because it further lowers anterior chamber pH and worsens the process. Emergent ophthalmologic consultation and admission to the hospital are warranted for hyphema.
Transfusions in SCD
The role of blood transfusions in SCD is constantly evolving. Indications for transfusions are based on sound clinical research and others on antecdotal reports of efficacy. However, there is little doubt that some complications of SCD require emergent blood transfusion. It is important for the emergency physician to understand the goals, indications, and effects of blood transfusion on the disease process in person with SCD.
In patients without SCD undergoing blood transfusions, oxygen transport increases as blood is transfused until the hematocrit (HCT) reaches 40%. Once the HCT reaches 45%, the viscosity increases dramatically and oxygen transport starts to fall. In patients with SCD, the viscosity of an RBC suspension at full oxygenation is already higher than that of an Hb AA RBC suspension, and the viscosity of the sickle RBC suspension rises progressively with deoxygenation.
When a patient with SCD receives a simple blood transfusion, the increase in HCT with a constant sickle crit (Sct) leads to an increase in viscosity, thus limiting the improvement of oxygen delivery, despite the improved oxygen carrying capacity. It appears that a Sct of greater than 25% causes a disproportionate increase in whole-blood viscosity related to increasing HCT as compared with Hb AA patients. Thus, in the non-anemic patient with SCD, exchange transfusion instead of simple transfusion results in more efficient delivery of oxygen to tissues.
Simple blood transfusion is indicated in patients with SCD whose hemoglobin levels drops sufficiently to give rise to clinical compromise such as congestive cardiac failure and hypovolemic shock. It is rarely necessary to transfuse an SS patient if the hemoglobin level is greater than 5.0 g/dL, unless there is a reticulocytopenia associated with the falling hemoglobin or clinical evidence that the fall will continue.
In the United States and United Kingdom, the most common cause of an acute fall in hemoglobin is related to the following sequestration syndromes: 1) Splenic sequestration, which most commonly occurs in SS infants; 2) hepatic sequestration, which is more common in adolescents and adults and is associated with septicemia; 3) the acute chest syndrome; and 4) the mesenteric syndrome. Aplastic crisis, generally caused by infection with parvovirus B-19, often occurs within families. In these cases, raising the hemoglobin to between 9 and 10 g/dL by a single transfusion is generally sufficient. In general, a simple transfusion should be used to return the patients hemoglobin to his or her stable state level. The volume to be transfused can be calculated from the following equation:
Volume of RBCs (mLs) = (Hbd - Hbs) ´ weight (kg) ´ K*
K* is a constant depending on the hematocrit of blood to be transfused (K = 3 if packed red cells; K = 4 if plasma reduced blood; K = 6 if whole blood).
Hbd is desired hemoglobin in g/dL.
Hbs is starting hemoglobin in g/dL.
Exchange transfusions are more complex procedures and involve the removal of whole blood which is then replaced with RBC and crystalloid. Exchange transfusions are generally not performed in the province of the emergency department due to the logistics and time needed to prepare for the procedure. Typically, 7-8 units of blood are needed and vascular access with a Quinton catheter is needed for automated systems. However, it is important for the emergency physician to know the indications for this procedure. (See Table 4.)
Disposition
Whether to admit a patient with an acute complication of SCD is often a matter of clinical judgment with input from the patient’s hematologist. However, in general, patients who have uncontrolled painful crisis, aplastic anemia, splenic sequestration, acute focal neurological deficit, or signs of infection should be admitted to the hospital. (See Table 5.)
Summary
SCD is a group of genetic disorders which can affect every organ system. Emergency physicians who care for these patients must be familiar with the variety of acute crises as well as chronic manifestations of this condition. It is important to remember that the "repeat sickler" who presents to the emergency department on multiple occasions, who has the most severe disease, and is at increased risk for complications and early death.
In children with SCD, clinical diligence and a low threshold for consultation will serve the emergency physician well. Mortality is greatest in the 1- to 3-year-old age group, and unusual pathology such as stroke and sequestration crisis may be life threatening. It is hoped that new therapies such as bone marrow transplantation and hydroxyurea will ameliorate the effect of this disease on these patients.
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Physician CME Questions
33. The most common cause of death in adult patients with sickle cell disease is:
A. acute cerebrovascular accident.
B. acute chest syndrome.
C. acute splenic sequestration crisis.
D. high-output cardiac failure.
E. sickle cell intrahepatic cholestasis.
34. In adult patients, all of the following are associated with increased risk of early death in sickle cell anemia except:
A. acute chest syndrome.
B. baseline WBC above 15,000 cell/m3.
C. high level of fetal hemoglobin.
D. renal failure.
E. seizures.
35. Which of the following concerning acute splenic sequestration crisis is incorrect?
A. It is uncommon in adults with HbSS disease.
B. It is classically defined as an increase in hemoglobin concentration of at least 2g/dL.
C. Laboratory studies usually reveal a marked reticulocytosis.
D. Clinical findings may include sudden weakness, pallor of lips and mucous membranes, tachycardia, tachypnea, and abdominal fullness.
36. Which of the following statements concerning Acute CVA in sickle cell disease is correct?
A. Recurrent stroke in children is most common one year after the initial stroke.
B. Ischemic stroke is most common in children.
C. Simple transfusions is indicated in children with ischemic stroke.
D. Stroke in adults with SCD is usually due to large vessel occlusion.
E. In children, stroke is most common in the 6-month to 1-year age group.
37. Which of the following statements about acute chest syndrome is correct?
A. Acute chest syndrome only occurs in adults.
B. Adult patients are usually febrile.
C. Rib and sternal infections, and fat and/or pulmonary emboli have all been identified as causes.
D. Hydroxyurea has no affect on the incidence of acute chest syndrome.
38. Which of the following is correct concerning the use of meperidine in the treatment of acute vaso-occlusive crisis?
A. Meperidine is the least commonly used analgesic in the emergency department management of acute vaso-occlusive crisis.
B. Nor-meperidine has a half-life that is one-half that of meperidine.
C. Nor-meperidine is a toxic metabolite of meperidine which can cause seizures.
D. Meperidine does not accumulate in patients with normal renal function.
E. Meperidine is the drug of choice for the treatment of acute vaso-occlusive crisis.
39. All of the following concerning acute vaso-occlusive crisis are true except:
A. most patients with SCD are able to treat most of their painful episodes at home.
B. no specific laboratory test is pathognomonic of painful crisis.
C. oxygen therapy is indicated in all patients with painful crisis.
D. acute painful crisis is responsible for 90% of hospital admissions in patients with SCD.
E. factors known to precipitate acute painful episodes include dehydration, infection, and psychological stress.
40. Which of the following is true of transfusions in SCD?
A. Patients with SCD should be transfused to a HCT of 40-45% for optimal oxygen carrying capacity.
B. Exchange transfusion are indicated in adults with hemorrhagic strokes.
C. Aplastic crisis is initially treated with exchange transfusion.
D. Patients with SCD with severe, symptomatic anemia usually require simple blood transfusion.
E. It is recommended that priapism be treated with red cell transfusion.
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