eMedicine Specialties > Emergency Medicine > Hematology & Oncology
Anemia, Sickle Cell
Updated: Nov 16, 2009
Introduction
Background
Sickle cell disease (SCD), the most common monogenetic disorder worldwide, affects an estimated 30 million persons and represents a major public health concern because of its associated significant morbidity and mortality. Modern advances in molecular and cellular biology have generated increasing knowledge of the pathophysiological basis for this disease with heterogeneous manifestations and have paved the route to the development of novel and targeted therapeutic interventions. With the increasing knowledge about this disease, it is imperative that emergency physicians orient themselves with the varied clinical presentations and the new insights into pathophysiology and treatment of this disorder.
Peripheral blood smear with sickled cells at 1000X magnification. Photograph by Dr Ulrich Woermann.
Genetics Sickle cell disease denotes all genotypes containing at least one sickle gene, in which hemoglobin S (HbS) makes up at least half the hemoglobin (Hb) present. Major sickle genotypes described so far include the following:
- HbSS disease or sickle cell anemia (the most common form) - Homozygote for the S globin with usually a severe or moderately severe phenotype with the shortest survival
- HbS/B° thalassemia - Double heterozygote for HbS and B° thalassemia and clinically indistinguishable from sickle cell anemia (SCA)
- HbS/B+ thalassemia - Mild-to-moderate severity with variability in different ethnicities
- HbSC disease - Double heterozygote for HbS and HbC characterized by moderate clinical severity
- HbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotype
- HbS/HbE syndrome - Very rare with a phenotype usually similar to HbS/B+ thalassemia
- Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others
Sickle cell trait or the carrier state is the heterozygous form characterized by the presence of around 40% HbS, absence of anemia, inability to concentrate urine, and hematuria. Under conditions leading to hypoxia, it may become a pathologic risk factor.
Pathophysiology
The molecular defect of sickle cell disease was unraveled more than 50 years ago. A single nucleotide substitution (GTG for GAG) in the sixth codon of the beta-globin gene results in a single amino acid substitution of valine for glutamic acid leading to HbS formation. Upon deoxygenation, HbS, which is less soluble than normal HbA, undergoes polymerization leading to the characteristic sickle cell. The polymerization of deoxygenated HbS is the primary indispensable event in the molecular pathogenesis of sickle cell disease but is an insufficient determinant of phenotype. HbS polymerization is associated with increased red cell density (dense erythrocytes) as well as red cell membrane damage favoring the generation of distorted rigid sickle cells and contributing to vaso-occlusion and premature red cell destruction (hemolytic anemia).
Vaso-occlusion involves a complex interaction of sickle and nonsickle erythrocytes, reticulocytes, leukocytes, platelets, plasma factors, and endothelial cells driven by inflammatory mediators through the up-regulation of adhesion molecules. Leukocyte adhesion in small post capillary venules is emerging as a key factor that contributes to vaso-occlusion and offers an attractive therapeutic target for SCD.
Molecular and cellular changes of hemoglobin S.
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Hemolysis
Sickle cell disease is a form of hemolytic anemia with red cell survival of around 10-20 days. Approximately one third of the hemolysis occurs intravascularly releasing free hemoglobin (plasma free hemoglobin [PFH]) and arginase into plasma. PFH has been associated with endothelial injury including scavenging NO, proinflammatory stress, and coagulopathy, resulting in vasomotor instability and proliferative vasculopathy.
A hallmark of this proliferative vasculopathy is the development of pulmonary hypertension (PH) in adulthood. Plasma arginase degrades arginine, the substrate for NO synthesis, thereby limiting the expected compensatory increase in NO production and resulting in generation of oxygen radicals. Plasma arginase is also associated with pulmonary hypertension and risk of early mortality.
Clinical presentation
Sickle cell disease is a highly phenotypically variable disease. Some individuals have very severe disease with frequent vaso-occlusive complications and early morbidity and death at a very young age, whereas, in others, the disease can go unnoticed until adulthood. This single missense mutation disease can have wide-ranging manifestations and complications that affect every aspect of the life of affected patients. Natural history studies determined features of the disease and identified risk factors for disease-related morbidity and mortality.1,2,3 Key clinical manifestations are attributed to two major subphenotypes, one attributed to vaso-occlusion and another to hemolysis.
The vaso-occlusive subphenotype is manifested clinically by self-limited pain (vaso-occlusive) episodes, acute chest syndrome (ACS), joint necrosis, stroke, acute splenic sequestration (ASS), hepatic sequestration, and organ failure as renal disease and functional asplenia. Manifestations of the hemolytic subphenotype, on the other hand, are chronic anemia, gallstones, pulmonary hypertension, priapism, leg ulceration, sudden death, and possibly stroke. The most common causes of disease-related morbidity are pain and acute chest syndrome episodes. Pulmonary complications also contribute significantly to premature death.
Vaso-occlusive crises
Pain
A vaso-occlusive crisis occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and is clinically translated as pain. Pain crises constitute the most distinguishing clinical feature of sickle cell disease and are the first cause of emergency department visits and hospitalizations for affected patients. Pain crisis can involve the abdomen, bones, joints, and soft tissue, and it may present as dactylitis (bilateral painful and swollen hands and/or feet in children), acute joint necrosis, or acute abdomen.4 With repeated episodes in the spleen, infarctions, and autosplenectomy predisposing to life-threatening infection are usual. The liver also may infarct and progress to failure with time. Papillary necrosis is a common renal manifestation of vaso-occlusion, leading to isosthenuria (ie, inability to concentrate urine).
Acute chest syndrome
Vaso-occlusive crises can also involve the lungs and result in acute chest syndrome (ACS), defined as a new infiltrate on chest radiograph associated with fever or respiratory symptoms. Acute chest syndrome affects about 40% of all people with SCA and has become the most common reason for early mortality. It may be a presenting diagnosis but often develops after acute infections, painful episodes, rib or bone marrow or pulmonary infarction, surgery, and fat embolism. Previous episodes of acute chest syndrome increase the likelihood of repeated acute pulmonary events and subsequent pulmonary hypertension. Asthma and airway hyperreactivity seem to be associated with recurrent acute chest syndrome and pain.
Young children present with fever, cough, and upper lobe disease in contrast to adults who are usually afebrile and dyspneic with severe chest pain and multilobar and lower lobe disease. Overall death rate from acute chest syndrome is 1.8% and 4 times higher in adults than in children. Causes of death are pulmonary embolism and infection.
Stroke
Stroke is one of the most devastating complications of sickle cell disease and a leading cause of morbidity and mortality among affected children. It affects 30% of children and 11% of patients by 20 years and is mostly seen in SCA. It is usually ischemic in children and hemorrhagic in adults.5 Transcranial Doppler (TCD), which measures blood flow velocity in the large arteries of the circle of Willis, can detect children at risk of developing stroke months to years before the stroke and/or before magnetic resonance angiography (MRA) changes. Velocity, which is usually increased by severe anemia, becomes elevated in a focal manner when stenosis reduces the arterial diameter. As for silent cerebral infarcts, defined as MR imaging evidence of ischemia with no clinical signs and symptoms, these are seen in around 20% of SS children and can be associated with poor performance on neuropsychological tests and high risk of developing stroke.
Infections
Life-threatening bacterial infections are a major cause of morbidity and mortality in patients with sickle cell disease. Recurrent vaso-occlusion induces splenic infarctions and consequent autosplenectomy predisposing to severe infections with encapsulated organisms (eg, Haemophilus influenzae, Streptococcus pneumoniae). Lower serum immunoglobulin M (IgM) levels, impaired opsonization, and sluggish alternative complement pathway activation further increase susceptibility to other common infectious agents, including Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli.
Pneumococcal sepsis continues to be a major cause of death in infants in some countries. Parvovirus B19 infection causes aplastic crises. Neonatal screening, penicillin prophylaxis, appropriate immunizations particularly against pneumococcus, and parental teaching have remarkably minimized infection-related morbidity and mortality.
Pulmonary hypertension
Pulmonary hypertension, defined as a tricuspid regurgitant jet velocity (TRJV) >2.5 m/s on echocardiography, is an emergent complication seen in 32% of adult patients with sickle cell disease and is associated with a high mortality rate. Pulmonary hypertension is a complication of chronic intravascular hemolysis. Additional factors contributing to pulmonary hypertension include older age, renal insufficiency, cardiovascular disease, cholestatic hepatopathy, systolic hypertension, high hemolytic markers, iron overload, and a history of priapism. Even modestly increased pulmonary artery pressures are associated with severe reduction in exercise capacity, as assessed by both the 6-minute walk and cardiopulmonary exercise testing, and do herald a poor prognosis. Both pulmonary hypertension and cardiac sequelae, such as diastolic dysfunction, have been associated with accelerated mortality in the sickle cell disease population.
Acute splenic sequestration
This life-threatening complication, seen in the first few years of life and resulting in circulatory collapse and death from anemia and hypovolemic shock, is defined as a sudden enlargement of the spleen with a decrease in Hb concentration (2 g/L at least) and substantial reticulocytosis. Early parental recognition of the signs and symptoms of this complication and its prompt therapy significantly decrease its associated morbidity and mortality
Aplastic crises
Severe anemia due to temporary cessation of erythropoiesis is seen mostly with parvovirus B19 infection.
Priapism
This is a well-described complication of sickle cell disease that leads to impotence and is difficult to manage. Priapism is a painful failure of detumescence clinically presenting as either scattered episodes, or a stuttering pattern, usually nocturnal with progressive clustering of more intense episodes over a short period.
Survival
The cooperative study of SCD (CSSCD) estimated that the median survival for individuals with SS was 48 years for women and 42 years for men.6 In the Dallas newborn cohort, estimated survival at 18 years was 94%. In a recent neonatal UK cohort followed in a hospital and community-based program including modern therapy with TCD screening, the estimated survival of HbSS children at 16 years was 99.0.
This significant increase in life expectancy and survival of patients with sickle cell disease has been achieved thanks to early detection and introduction of disease-modifying therapies. Neonatal screening, penicillin prophylaxis for children, pneumococcal immunization, red cell transfusion for selected patients and chelation therapy, hydroxyurea therapy, parental and patient education and, above all, treatment in comprehensive centers have all likely contributed to this effect on longevity. However, as patients with sickle cell disease get older, new chronic complications are appearing. Pulmonary hypertension is emerging as a relatively common complication and is one of the leading causes of morbidity and mortality in adult sickle cell disease.
Predictors of disease severity
Multiple cellular and genetic factors contribute to phenotypic heterogeneity. These include low HbF, dactylitis, severe anemia, leukocytosis, childhood asthma, abnormal TCD, and prolonged TRJV are all associated with severe disease. Disease ameliorating factors are coinheritance of α–thalassemia, β-thalassemia, β-C gene interaction, and specific β-globin haplotypes.
Frequency
United States
Incidence of the homozygous state among black newborns is about 0.8%. Approximately 8% of blacks carry the mutated gene.
Mortality/Morbidity
Data from Quinn et al (2004) suggest improvement in mortality rates for patients with sickle cell disease over the past 30 years.7 Recent information suggests 85% survival to age 18 years. This study tracked 700 children for 18 years.
Earlier data reported that, among patients with sickle cell disease, approximately 50% do not survive beyond age 20 years, and most do not survive to age 50 years.Race
The highest incidence of sickle cell disease is in those of African descent.
Sex
No sex predilection exists, since sickle cell anemia is not an X-linked disease.
Clinical
History
- Pain is the most common presentation of vaso-occlusive crisis. Inquire about pain location, duration and mode of onset (acuity of onset), character, and previous similar episodes.
- Infections: Ask about, fever, cough, neck stiffness and severe headache (concerning for meningitis), and urinary symptoms (polyuria, hematuria, dysuria).
- Acute chest syndrome: Inquire about shortness of breath or dyspnea, fever, and cough.
- Stroke: Ask about aphasia, paresthesias, limb weakness, and change of level of consciousness.
- ASS: Inquire about noticeable increase in weakness or pallor, syncope, and sudden abdominal distention.
- Previous intake of analgesics (type and dose, if possible) and folic acid
- Surgical history (helps rule out other causes of abdominal pain)
- Previous hemoglobin levels and previous transfusions
- Vaccination
- Consanguinity, family history of similar episodes
Physical
- Vital signs
- Hypotension and tachycardia may be signs of septic shock or splenic sequestration crisis. With the severe anemia that accompanies aplastic crisis, patients may exhibit signs of high-output congestive heart failure (CHF).
- Orthostasis suggests hypovolemia.
- Tachypnea suggests pneumonia, CHF, or acute chest syndrome. Hypoxia was commonly seen in patients with acute chest syndrome.
- Dyspnea suggests acute chest syndrome, pulmonary hypertension, and/or CHF.
- Fever suggests infection in children; however, it is less significant in adults unless it is a high-grade fever.
- Examine head and neck for meningeal signs or possible source of infection (eg, otitis, sinusitis).
- Auscultate the heart to search for signs of congestive heart failure.
- Auscultate the lungs to search for signs of pneumonia, CHF, or acute chest syndrome (similar to pulmonary embolism).
- Palpate for tenderness (abdomen, extremities, back, chest, femoral head) and hepatosplenomegaly.
- Observe for pallor, icterus, and erythema or edema of the extremities or joints.
- Perform a neurological examination to search for focal neurological deficits.
- Look for evidence of retinopathy on funduscopy.
Causes
- Vaso-occlusive crises are often precipitated by the following:
- Cold weather (due to vasospasm)
- Hypoxia (flying in unpressurized aircraft)
- Infection
- Dehydration (especially from exertion or during warm weather)
- Acidosis
- Alcohol intoxication
- Emotional stress
- Pregnancy
- Data also suggest a role for exertional stress, particularly when compounded with heat and hypovolemia.
- Aplastic crises are often preceded by the following:
- Infection with parvovirus B19
- Folic acid deficiency
- Ingestion of bone marrow toxins (eg, phenylbutazone)
- Acute chest syndrome has been linked to fat embolism and infections, pain episodes, and asthma.8
Differential Diagnoses
| Acute Coronary Syndrome | Pneumonia, Bacterial |
| Anemia, Acute | Pneumonia, Empyema and Abscess |
| Anemia, Chronic | Pneumonia, Immunocompromised |
| Appendicitis, Acute | Pneumonia, Mycoplasma |
| Cholecystitis and Biliary Colic | Pneumonia, Viral |
| Gout and Pseudogout | Priapism |
| Hepatitis | Pulmonary Embolism |
| Meningitis | Rheumatic Fever |
| Osteomyelitis | Stroke, Ischemic |
| Pancreatitis | Subarachnoid Hemorrhage |
| Pelvic Inflammatory Disease | Urinary Tract Infection, Female |
| Pneumonia, Aspiration | Urinary Tract Infection, Male |
Other Problems to Be Considered
Aplastic crisis
Septic arthritis
Chronic splenomegaly
Pulmonary infarction
Rib infarction
Sepsis
Splenic sequestration
Synovial thrombosis
Upper respiratory tract infection
Workup
Laboratory Studies
- Assess hemoglobin and hematocrit levels. Anemia is often identified; however, a major drop in hemoglobin (ie, more than 2 g/dL) from previously recorded values indicates a hematological crisis. If the reticulocyte count is normal, splenic sequestration is the probable cause. If the reticulocyte count is low, an aplastic crisis is the probable cause. If the reticulocyte count is high, hyperhemolytic crises is the probable cause.
- Obtain a leukocyte count. Leukocytosis is expected in all patients with sickle cell anemia. Major elevation in the WBC count (ie, >20,000 per mm3) with a left shift raises suspicion for infection. Leucopenia is suggestive of parvovirus infection.
- The platelet count is often elevated. If low, consider of hypersplenism.
- In a peripheral smear, sickle-shaped RBCs are found along with target cells and nucleated red cells. Concomitant microcytosis and basophilic stippling are seen in sickle beta-thalassemia. Presence of Howell-Jolly bodies indicates that the patient is asplenic.
Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Photograph by Dr Ulrich Woermann.
- Arterial blood gases (ABGs) may be obtained in patients who are in respiratory distress to supplement information provided by oxygen saturation monitoring. This will reflect the severity of pulmonary crisis. Serial ABGs are necessary to follow the response in pulmonary crisis.
- Obtain liver function tests in patients with abdominal pain. An elevated baseline indirect bilirubin level may be normal because of chronic hemolysis.
- Type and crossmatch in case transfusion is necessary.
- Perform urinalysis if the patient has fever or signs of urinary tract infection (UTI). Patients with sickle cell anemia often have hematuria and isosthenuria. If signs of urinary tract infection are present, obtain a urine Gram stain and culture.
- If the diagnosis of sickle cell anemia is uncertain, a sickling test will establish the presence of HbS gene. It will not, however, differentiate between individuals who are homozygous and those who are heterozygous.
- Hemoglobin electrophoresis, though not immediately useful in the ED, differentiates individuals who are homozygous from those who are heterozygous.
- A homozygous patient will have hemoglobin SS (HbSS, 80-90%), hemoglobin F (HbF, 2-20%), and hemoglobin A2 (HbA2, 2-4%).
- A carrier patient will have HbSS (35-40%) and hemoglobin A (HbA, 60-65%).
- The test is not accurate in a patient who has recently received blood transfusions.
- Secretory phospholipase A2 (sPLA2), an enzyme that cleaves fatty acids from triglycerides, is an accurate marker for identifying present or incipient acute chest syndrome in young patients with sickle cell pain crises . Its serum concentration increases before acute chest syndrome becomes clinically apparent, peaks at the clinical onset of acute chest syndrome, and declines during its resolution.
Imaging Studies
- Chest radiography
- Perform in patients with respiratory symptoms.
- Radiographic findings may initially be normal in patients with acute chest syndrome.
- Bone radiography
- Perform in patients with localized bone tenderness.
- Do not differentiate between osteomyelitis and bone infarction in the early stages. Radiographic signs of osteomyelitis may not appear for 8-10 days.
- A view of the vertebral column shows typical fish-mouth appearance of vertebrae in patients with sickle cell anemia. This is due to expansion of the bone marrow.
- Ultrasonography
- Use in patients with abdominal pain to rule out cholecystitis, cholelithiasis, or an ectopic pregnancy and to measure spleen and liver size.
- Assess liver and spleen size.
- Cardiac echo should be performed for patients with dyspnea.
- Head CT or MRI is used if signs and symptoms of stroke are present.
- Bone scans can aid in early differentiation of bone infarction and osteomyelitis.
Treatment
Prehospital Care
- When severity of the patient's crisis is assessable, self-treatment at home with bed rest, oral analgesia, and hydration is possible.
- Individuals with sickle cell anemia often present to the ED after failing self-treatment. Do not underestimate the patient's pain.
- If patients with sickle cell anemia are in crisis and are being transported by EMS, they should receive supplemental oxygen and intravenous hydration en route to the hospital.
Emergency Department Care
Some areas have specialized facilities that offer emergency care of acute pain associated with sickle cell disease; many emergency departments (EDs) have a standardized treatment plan in place. Failure to treat acute pain aggressively and promptly may lead to chronic pain syndrome. Pain management should include 4 stages: assessment, treatment, reassessment, and adjustment. While considering the severity of pain and the patient's past response, follow consistent protocols to relieve the patient's pain.
Treatment of pain crises is primarily pharmacologic in nature, and opioids represent the mainstay of therapy. Hydration is another mainstay of treatment. For mild-to-moderate pain, acetaminophen with codeine or a nonsteroidal anti-inflammatory drug (NSAID) is usually enough. Patients with severe pain should be given a parenteral opiate in full therapeutic doses at fixed intervals (and not as needed) until pain diminishes at which time the opiate is tapered and then stopped and oral analgesic therapy is instituted. If more frequent doses are needed, patient-controlled analgesia (PCA) can be used. For all types of pain, incentive spirometry is recommended. For frequent and severe pain, long-term hydroxyurea (HU) is presently the accepted treatment.9 For HU nonresponders, chronic transfusions for a limited period may be an option. Management of constant pain is extremely difficult, and expert advice should be obtained.
Effects of therapy with hydroxyurea.
Treatment of acute chest syndrome consists of oxygen, antibiotics, incentive spirometry, simple transfusion, and bronchodilators. Exchange transfusion may be indicated for severe cases. Adults, in general, need a higher rate of transfusions and longer hospitalization as compared to children. Overhydration must be avoided.
As for stroke, blood transfusion therapy, aimed at keeping HgbS at less than 30%, is now considered standard care for primary and secondary stroke prevention in children with sickle cell disease. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) showed that regular blood transfusions produced a marked (90%) reduction in first stroke in asymptomatic high-risk children who had 2 abnormal transcranial Doppler (TCD) studies with velocities of 200 cm/s or greater.10 During the transfusion period, most of the TCD studies reverted to or toward normal, but, once transfusion was stopped, there was an unacceptably high rate of TCD reversion to high risk, as well as to actual strokes.11
Prompt recognition and treatment of acute splenic sequestration (ASS) with immediate transfusion have reduced the number of deaths attributed to this life-threatening medical emergency. All new mothers should be educated about symptoms of this potentially life-threatening event and how to do splenic palpation on their infant.
As for priapism, early exchange transfusion is indicated. Epidural neuraxial blockade offers superior analgesia to the often painful conservative treatments. Surgical intervention is the last therapeutic option and often results in significant long-term morbidity.12,13 Intermittent treatment with phosphodiesterase 5 (PDE5) inhibitors is hypothesized to increase PDE5 protein expression, which relieves priapism in pilot studies in patients with sickle cell disease.
Oxygen supplementation is only beneficial if the patient has hypoxia. Intubation and mechanical ventilation may be required in patients in whom strokes have occurred and in patients with acute chest syndrome.
Transfusions are not needed for the usual anemia or episodes of pain associated with sickle cell disease. Urgent replacement of blood is often required for sudden severe anemia due to ASS, parvovirus B19 infection, or in hyperhemolytic crises. Transfusion is helpful in acute chest syndrome, perioperatively and during pregnancy. Acute red cell exchange transfusion is indicated in acute infarctive strokes, severe acute chest syndrome and the multi-organ failure syndromes, the right upper quadrant syndrome, and possibly priapism. Transfusions, simple or exchange, are unlikely to speed up resolution of an acute pain episode. Exchange blood transfusions are indicated in cases of strokes and acute chest syndrome. They are performed occasionally in patients with acute sequestration crisis or in cases of priapism that do not resolve after adequate hydration and analgesia.Consultations
- Consultation with a hematologist may be necessary.
- If retinopathy or hyphema is suspected and visual symptoms are present, consultation with an ophthalmologist is warranted.
- In case of priapism that does not resolve after 6 hours of hydration and analgesia, consult a urologist for aspiration of corpus cavernosum or shunting.
- If avascular necrosis of the hip is suspected in a patient with hip pain and difficulty in walking, consult an orthopedist for possible hip joint replacement. Consult an orthopedist if osteomyelitis is suspected.
Medication
Medications involved in the treatment of sickle cell anemia include analgesics for pain and antibiotics for infections.
Analgesics
Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties.
Codeine
Binds to opiate receptors in CNS, causing inhibition of ascending pain pathways, altering perception and response to pain.
Dosing
Adult
15-60 mg PO/IV/IM/SC q4-6h; not to exceed 120 mg/d
Pediatric
0.5 mg/kg PO/IM/SC q4-6h
Interactions
Phenothiazines may decrease analgesic effect; conversely, acetaminophen toxicity can increase when administered concurrently with CNS depressants or tricyclic antidepressants
May potentiate CNS effects of barbiturates
Contraindications
Documented hypersensitivity; HACE diagnosis; elevated intercostal pain
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use to treat cough in patients with HAPE only if absolutely necessary; may depress hypoxic ventilatory rate and respiratory drive during sleep
Aspirin (Anacin, Ascriptin, Bayer)
Treats mild to moderate pain. Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.
Dosing
Adult
325-600 mg PO q4h
Pediatric
10-15 mg/kg/dose PO q4-6h; not to exceed 60-80 mg/kg/d
Interactions
Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Contraindications
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; because of association of aspirin with Reye syndrome, do not use in children (<16 y) with flu
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or who are taking anticoagulants
Acetaminophen (Tylenol, Panadol, Aspirin Free Anacin)
DOC for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.
Dosing
Adult
325-650 mg PO q4-6h; not to exceed 4 g/d
Pediatric
<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d
>12 years: 325-650 mg PO q4h; not to exceed 5 doses/d
Interactions
Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Contraindications
Documented hypersensitivity; known G-6-P deficiency
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Hepatotoxicity possible in chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; acetaminophen is contained in many OTC products and combined use with these products may result in cumulative acetaminophen doses exceeding recommended maximum dose
Ibuprofen (Ibuprin, Advil, Motrin)
Usually the DOC for treatment of mild to moderate pain, if no contraindications exist. Inhibits inflammatory reactions and pain by decreasing the activity of the enzyme cyclo-oxygenase, resulting in inhibition of prostaglandin synthesis.
Dosing
Adult
200-800 mg PO qd
Pediatric
Children's Motrin
2-3 years: 1 tsp
4-5 years: 1 1/2 tsp
6-8 years: 2 tsp
9-10 years: 2 1/2 tsp
12 years: 3 tsp
>12 years: Administer as in adults
Interactions
Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Contraindications
Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy
Oxycodone and acetaminophen (Percocet, Roxicet, Roxilox)
Drug combination indicated for the relief of moderate to severe pain. DOC for patients who are hypersensitive to aspirin.
Dosing
Adult
1 tab PO q4-6h prn
Pediatric
0.05-0.15 mg/kg/dose oxycodone PO; not to exceed 5 mg/dose oxycodone
Interactions
Phenothiazines may decrease analgesic effects of this medication; toxicity increases with coadministration of either CNS depressants or tricyclic antidepressants
Contraindications
Documented hypersensitivity; CNS injuries
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Duration of action may increase in elderly persons; be aware of total daily dose of acetaminophen patient is receiving; do not exceed 4,000 mg/24 h of acetaminophen; higher doses may cause liver toxicity
Meperidine (Demerol)
Analgesic with multiple actions similar to those of morphine; may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.
Dosing
Adult
50-150 mg PO/IV/IM q3-4h prn
Pediatric
1-1.8 mg/kg IM q1-3h
Interactions
Monitor for increased respiratory and CNS depression with coadministration of cimetidine; hydantoins may decrease effects of meperidine; avoid with protease inhibitors
Contraindications
Documented hypersensitivity; MAOIs; upper airway obstruction or significant respiratory depression; during labor when premature delivery of infant is anticipated
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with head injuries since meperidine may increase respiratory depression and CSF pressure (use only if absolutely necessary); caution when using postoperatively and with history of pulmonary disease (suppresses cough reflex)
Substantially increased dose levels, due to tolerance, may aggravate or cause seizures even if no prior history of convulsive disorders exists; monitor closely for morphine-induced seizure activity if prior seizure history
Morphine sulfate (Duramorph, Astramorph, MS Contin)
DOC for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Various IV doses are used; commonly titrated until desired effect obtained.
Dosing
Adult
2- to 5-mg increments IV titrated q10-30min to pain response
30 mg PO q8-12h
10 mg/70 kg IM q4h
12-25 mg/70 kg in 5 mL of water over 5-min continuous infusion 0.1-1 mg/mL in 5% dextrose
Pediatric
0.1-0.2 mg/kg IV q4h; not to exceed 15 mg
Interactions
Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants, MAOIs, and other CNS depressants may potentiate adverse effects of morphine
Contraindications
Documented hypersensitivity; hypotension; potentially compromised airway in which establishing rapid airway control would be difficult
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Avoid in hypotension, respiratory depression, nausea, emesis, constipation, and urinary retention; caution in atrial flutter and other supraventricular tachycardias; has vagolytic action and may increase ventricular response rate
Oxycodone and aspirin (Percodan, Roxiprin, Codoxy)
Drug combination indicated for the relief of moderate to severe pain.
Dosing
Adult
1-2 tab or cap PO q4-6h prn pain
Pediatric
0.05-0.15 mg/kg/dose oxycodone PO; not to exceed 5 mg/dose of oxycodone q4-6h prn
Interactions
Phenothiazines may decrease analgesic effects; conversely, toxicity increases when administered concurrently with, CNS depressants or tricyclic antidepressants; may also potentiate anticoagulant effects of warfarin
Contraindications
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; children <16 y with the flu (potential risk of Reye syndrome)
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Duration of action may increase in elderly persons; caution in renal or liver impairment, peptic ulcer disease, and erosive gastritis
Methadone (Dolophine)
Used in the management of severe pain. Inhibits ascending pain pathways, diminishing the perception of and response to pain.
Dosing
Adult
2.5-10 mg PO/IM/SC q3-8h prn; increase to a maintenance dose of 5-20 mg q6-8h
Pediatric
0.7 mg/kg/d PO/IM/SC divided q4-6h prn; not to exceed 10 mg/dose
Interactions
Phenytoin, rifampin, and pentazocine may decrease blood levels of methadone; phenothiazines, tricyclic antidepressants, MAOIs, and CNS depressants may increase the toxicity of methadone
Contraindications
Documented hypersensitivity; bronchial asthma; increased intracranial pressure
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in severe liver disease; due to its relatively long half-life, titrate dose slowly
Antibiotics
These agents are used for treatment of suspected or confirmed infections.
Cefuroxime (Ceftin)
Second-generation cephalosporin that maintains gram-positive activity of first-generation cephalosporins and adds activity against P mirabilis, H influenzae, E coli, K pneumonia, and M catarrhalis. Condition of patient, severity of infection, and susceptibility of the microorganism should determine proper dose and route of administration.
Dosing
Adult
250 mg PO q12h or 750-1500 mg IV/IM q8h
Pediatric
125 mg PO q12h
50-100 mg/g/d IV/IM divided q6-8h
Interactions
Disulfiramlike reactions may occur when alcohol is consumed within 72 h after taking cefuroxime; may increase hypoprothrombinemic effects of anticoagulants; may increase nephrotoxicity in patient receiving potent diuretics such as loop diuretics; coadministration with aminoglycosides increases nephrotoxic potential
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Administer half dose if CrCl is 10-30 mL/min and one quarter dose if <10 mL/min; fungal and microorganism overgrowth may occur with prolonged therapy
Amoxicillin and clavulanate (Augmentin)
Drug combination that extends antibiotic spectrum of this penicillin to include bacteria normally resistant to beta-lactam antibiotics. Indicated for skin and skin structure infections caused by beta-lactamase-producing strains of S aureus. Administer treatment for a minimum of 10 d.
Dosing
Adult
250-500 mg PO q8h
Pediatric
<40 kg: 40 mg/kg PO divided tid
>40 kg: Administer as in adults
Interactions
Coadministration with warfarin or heparin increases risk of bleeding
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Increases risk of rash in patients taking allopurinol or with infectious mononucleosis
Perform bacteriologic studies to determine causative organisms and their susceptibility so that appropriate therapy is administered
Use therapy for a minimum of 10 d to eliminate organism; otherwise, sequelae such as endocarditis and rheumatic fever may ensue; cultures should be taken following treatment to confirm that the streptococci have been eradicated
Ceftriaxone (Rocephin)
Third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms.
By binding to one or more of the penicillin-binding proteins, arrests bacterial cell wall synthesis and inhibits bacterial growth.
Dosing
Adult
1-2 g IV/IM qd
Pediatric
50-75 mg/kg/d IV divided q12h; not to exceed 2 g/d
Interactions
Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adjust dose in renal impairment; caution in breastfeeding women and in those with penicillin allergy
Cefaclor (Ceclor)
Second-generation cephalosporin indicated for infections caused by susceptible gram-positive cocci and gram-negative rods.
Dosing
Adult
250-500 mg PO q8h
Pediatric
20-40 mg/kg/d PO divided q8-12h; not to exceed 2 g/d
Interactions
Alcoholic beverages consumed <72 h after taking cefaclor may produce disulfiramlike reactions; may increase hypoprothrombinemic effects of anticoagulants; coadministration with potent diuretics and aminoglycosides (eg, loop diuretics) may increase nephrotoxicity
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Reduce dosage by 1/2 if creatinine clearance is 10-30 mL/min and by 3/4 if <10 mL/min; bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged or repeated therapy
Antiemetics
These agents are useful in the treatment of symptomatic nausea.
Promethazine (Phenergan)
Used for symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in the treatment of emesis. Blocks postsynaptic mesolimbic dopaminergic receptors in the brain and reduces stimuli to brainstem reticular system.
Dosing
Adult
25 mg PO q4-6h prn
Pediatric
<2 years: Contraindicated
>2 years: 1 mg/kg PO q4-6h
Interactions
May have additive effects when used concurrently with other CNS depressants or anticonvulsants; coadministration with epinephrine may cause hypotension
Contraindications
Documented hypersensitivity; children <2 y (incidences of death due to respiratory depression)
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in cardiovascular disease, impaired liver function, seizures, sleep apnea, and asthma
Follow-up
Further Inpatient Care
- Indications for hospital admission for patients with sickle cell disease are as follows:
- Pulmonary, neurological, or infectious crisis
- Vaso-occlusive pain that does not resolve after 4-6 hours and 2 doses of narcotics in the ED
- Inability to maintain adequate hydration if discharged home
- Uncertain diagnosis
Further Outpatient Care
- If improvement is shown after 6 hours in the ED, patient may be discharged home with strict instructions to ingest large amounts of fluids and to return if pain recurs, temperature increases, or new symptoms develop.
- Arrange follow-up in a hematology clinic so that appropriate counseling can be given and new drugs, such as hydroxyurea, can be tried. Such drugs are believed to decrease the frequency of sickling crisis by increasing the percentage of fetal hemoglobin (HbF) in blood.
Inpatient & Outpatient Medications
- Folic acid should be prescribed to those who are not already taking it.
- Discharge the patient on oral analgesics for a week. Up to 2 doses of narcotics can be administered in the ED over a period of 4-6 hours.
- Oral drugs for mild pain include acetaminophen, ibuprofen, aspirin, and codeine. If pain is moderate, oxycodone or methadone can be administered.
- Administer parenteral drugs for severe pain. Morphine is the drug of choice, but meperidine with promethazine can be used.
- Antibiotics are indicated when an infection is suspected, when body temperature is higher than 38 degrees Celsius, or when a patient has localized bone tenderness. Fever in children is strongly suggestive of infection. It has been found that signs of infection are more accurate in children than in adults.
- Common infections include pneumonia, bronchitis, cholecystitis, pyelonephritis, cystitis, osteomyelitis, meningitis, and sepsis. Recommended parenteral antibiotics include cephalosporins (eg, ceftriaxone, cefuroxime) and macrolides for acute chest syndrome.
- If the patient is discharged home, oral antibiotics (eg, amoxicillin-clavulanic acid, clarithromycin, cefixime) are useful in selected cases. If the patient has localized bone tenderness, seek antibiotic coverage for S typhimurium and S aureus.
Transfer
- Transfer is only applicable if exchange transfusion or ICU is not available.
Deterrence/Prevention
- Measures to prevent sickle cell crisis include the following:
- Adherence to an immunization against pneumococcus, H influenzae, meningococcus, hepatitis B, influenza, and Salmonella typhi (in endemic areas) as well as routine vaccines.
- Avoid temperature extremes, high altitudes, and cold weather
- Enforce oral fluids
- Foot care and protective shoes
- Periodic health care visits and surveillance workups
- Educate parents and elderly patients about symptoms of life-threatening complications.
- Biannual medical visit for those older than 30 years
Complications
- Pulmonary hypertension, attributed to hemolysis and hypoxia and seen in adult patients, heralds a poor prognosis and is refractory to hydroxyurea therapy. Cor pulmonale may ensue, and the management is that of patients with right-sided heart failure and chronic obstructive pulmonary disease (COPD).
- Cholelithiasis may occur because gallstones form as a result of chronic hemolytic anemia. Ultrasonography is diagnostic. If symptomatic, cholecystectomy is indicated.
- Ophthalmologic complications include retinopathy, which can be proliferative and nonproliferative, as well as retinal infarcts and retinal detachment. Findings on ophthalmoscopic examination include corkscrew vessels in the conjunctiva and salmon patches on the retina.
- Transfusion-related complications include alloimmunization, exposure to pathogens, and iron overload. Therapy of iron overload is becoming easier with the new oral chelators.
- Leg ulcers may result from venous stasis and chronic hypoxia and may become infected. Management is the same as with other stasis ulcers.
- Avascular osteonecrosis may result from chronic hypoxia in weight-bearing joints, commonly the femoral head. Joint replacement is often necessary.
- Psychological problems
- Patients may experience depression, anxiety, and chronic pain behavior.
- Counseling is crucial. Ensure an appropriate physician-patient relationship.
- Anxiolytics and amitriptyline may be used.
Prognosis
- Most patients with sickle cell anemia experience bacterial infections, painful crisis, and fatigue secondary to chronic anemia.
- Half of patients with sickle cell anemia die when younger than 20 years. Most do not survive to the age of 50 years.
Patient Education
- Teach patients to seek medical care in certain situations, including the following:
- Persistent fever (>38.3°C)
- Chest pain, shortness of breath, nausea, and vomiting
- Abdominal pain with nausea and vomiting
- Persistent headache not experienced previously
- Patients should avoid the following:
- Alcohol
- Nonprescribed prescription drugs
- Cigarettes, marijuana, and cocaine
- Seeking help in multiple institutions
- For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Anemia and Sickle Cell Crisis.
Miscellaneous
Medicolegal Pitfalls
- Carriers may show evidence of hemoglobinopathy under severe stress and hypoxic states.
- Carriers may have leg ulcers, splenic infarcts, and hyphema.
- Sickle beta-thalassemia and sickle cell disease
- Patients with either of these disorders can have splenomegaly and delayed autoinfarction of the spleen.
- Patients with sickle beta-thalassemia tend to have more vaso-occlusive symptoms than do patients with sickle cell anemia.
- Patients with sickle beta-thalassemia tend to have more proliferative retinopathy, renal disease, acute chest syndrome, and avascular osteonecrosis than do patients with sickle cell disease.
Special Concerns
- Sickle cell disease and pregnancy
- Patients who are pregnant and have sickle cell disease are at increased risk for crisis, toxemia, pyelonephritis, thrombophlebitis, and spontaneous abortion compared to the general population.
- Prophylactic transfusion with special concern for folic acid replacement has been shown to decrease the incidence of vaso-occlusive crisis during pregnancy.
- In the past, pregnancy was strongly discouraged, and tubal ligation often was performed.
Multimedia
Media file 1: Molecular and cellular changes of hemoglobin S.
Media file 2: Effects of therapy with hydroxyurea.
Media file 3: Peripheral blood with sickled cells at 400X magnification. Photograph by Dr Ulrich Woermann.
Media file 4: Peripheral blood smear with sickled cells at 1000X magnification. Photograph by Dr Ulrich Woermann.
Media file 5: Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Photograph by Dr Ulrich Woermann.
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Keywords
sickle cell disease, sickle cell anemia, sickle cell treatment, sickle cell causes, sickle cell symptoms, blood disorder, crescent cell anemia, sickle cell, hemoglobin S, vasoocclusive crisis, avascular necrosis, isosthenuria, acute chest syndrome
Contributor Information and Disclosures
Author
Ali Taher, MD, Professor of Medicine, Division of Hematology and Oncology, Assistant to the Chair-Undergraduate Program, Department of Internal Medicine, American University of Beirut Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Adlette Inati Khoriaty, MD, Head, Division of Pediatric Hematology-Oncology, Medical Director, Children's Center for Cancer and Blood Diseases, Rafik Hariri University Hospital; Research Associate, Balamand University; Head of Post Bone Marrow Transplant Clinic and Consultant Hematologist, Chronic Care Center, Lebanon
Adlette Inati Khoriaty, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Hematology, European Hematology Association, and International Society of Hematology
Disclosure: Nothing to disclose.
Ziad N Kazzi, MD, Assistant Professor, Department of Emergency Medicine, Emory University; Medical Toxicologist, Georgia Poison Center
Ziad N Kazzi, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, and American College of Medical Toxicology
Disclosure: Nothing to disclose.
Medical Editor
Roy Alson, MD, PhD, FACEP, FAAEM, Associate Professor, Department of Emergency Medicine, Wake Forest University School of Medicine; Medical Director, Forsyth County EMS; Deputy Medical Advisor, North Carolina Office of EMS; Associate Medical Director, North Carolina Baptist AirCare
Roy Alson, MD, PhD, FACEP, FAAEM is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, North Carolina Medical Society, Society for Academic Emergency Medicine, and Wilderness Medical Society
Disclosure: Nothing to disclose.
Pharmacy Editor
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment
Managing Editor
Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians
Disclosure: Nothing to disclose.
CME Editor
John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Chief Editor
Jonathan Adler, MD, Attending Physician, Department of Emergency Medicine, Massachusetts General Hospital; Division of Emergency Medicine, Harvard Medical School
Jonathan Adler, MD is a member of the following medical societies: American Academy of Emergency Medicine and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
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