Chapter 65: Sickle Cell Disease: Acute Complications

Individuals are diagnosed with sickle cell disease (SCD) if they have one of several genotypes that result in at least half of their hemoglobin (Hgb) being Hgb S. Sickle cell anemia (SCA) refers to the condition associated with homozygosity for the Hgb S mutation (Hgb SS). Other Hgb mutations may occur with Hgb S causing a similar but milder condition. In SCA, the presence of intracellular hemoglobin S polymerization leads to chronic hemolytic anemia, vasoocclusive crises of varying severity and frequency with cumulative organ damage and systemic manifestations that include impairment in growth and development, susceptibility to infection, and reduced quality and duration of life

Segal JB et al. Hydroxyurea for the Treatment of Sickle Cell Disease. Rockville, MD: Agency for Healthcare Research and Quality, 2008 Feb. Report No. 08-E007

Epidemiology

Platt OS et al. N Engl J Med 1994;330:1639–1644 (3764 patients. followed to determine life expectancy)

Sickle Cell Research for Treatment and Cure. Bethesda, MD: NIH Publication No. 02-5214;2002:1–16

Dept. of Energy, Human Genome Project. www.nhlbi.nih.gov/resources/docs/scd30/scd30.pdf [accessed August 5, 2013]

Major Sickle Hemoglobinopathies: Laboratory Features

Acute Pain Syndrome

1. Most common type of pain

2. Unpredictably abrupt in onset

3. Sometimes migratory

4. Varies in intensity from a mild ache to a severe and debilitating pain

5. Acute pain may occur with chronic pain and frequent episodes of acute pain can resemble chronic pain

6. In adults, about one-third of episodes are associated with a preceding or concurrent infection

7. Factors that potentiate Hgb S polymerization may precipitate an acute painful episode. These factors include acidosis, hypoxia, and dehydration

Chronic pain

1. Caused by obvious pathophysiology (eg, leg ulcers, avascular necrosis, chronic osteomyelitis)

2. Intractable chronic pain with no obvious sign

Ballas SK. Current issues in sickle cell pain and its management. Hematology Am Soc Hematol Educ Program. 2007:97–105

Ballas SK. Semin Hematol 2001;38:307–314

Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle-Cell Disease, APS Clinical Practice Guidelines Series, No. 1. Glenview, IL: American Pain Society; 1999:1–98

Castro O et al. Blood 1994;84:643–649

Rees DC et al. Br J Haematol 2003;120:744–752

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Epidemiology

1. In SCD, pain is the most common complaint and reason for patients to consult doctors and to be admitted to the hospital

2. Among patients with SCD in the United States, an acute pain episode accounts for ~90% of visits to the ER and 70% of all hospitalizations

3. Mean rate per year of acute pain episodes

   Hgb SS (0.8)

   Hgb Sβ-thalassemia (1.0)

   Hgb SC (0.4)

4. The rate of painful crises increases over the first 3 decades of life and then declines as a consequence of the earlier mortality of adults with higher rates of pain

Treatment

Initial management of severe acute pain in the emergency department (ED)

1. Arrival at ED to time +15–20 minutes after arrival

   1. Assess for common SCD acute pain states

   2. Determine pain type (onset, duration, frequency)

      • (1) Pain is atypical for SCD: Determine related symptoms (look for infections, complication, other comorbidities and precipitating factors). Next, assess pain, treat, and conduct work-up to determine etiology

      • (2) Pain is typical for SCD: See next step

   3. Determine pain characteristics (intensity, location, and quality based on self-report)

      • (1) Assess self-reported pain with an instrument such as a visual analog scale (VAS), Wong-Baker Faces Pain Rating Scale, or a simple verbal descriptor scale (0–10 scale; 0 = none, 10 = worst imaginable)

   4. Obtain treatment history (home meds, acute pain, hospital care, meds in past 24 hours, out-of-home meds)

   5. Examine pertinent physical factors

   6. Summarize assessment of profile and select treatment (based on characteristics of episode, prior treatment history, and physical findings)

      • (1) Not on chronic opioid therapy: Start IV loading dose of short-acting opioid (eg, morphine or hydromorphone; see Table 61-1 for opioid dosages)

      • (2) On chronic opioid therapy: Select medication and loading dose based on overall assessment and prior treatment history. Patient and family often know what medications and dosage have been effective in the past. Next, start IV loading dose of short-acting opioid. Administer SC if insufficient venous access

      • (3) Begin IV hydration (see Acute Pain Syndrome, Notes Section)

2. Time +15–30 minutes after ED arrival

   1. Add combination therapy as indicated (eg, antiinflammatory and or antihistamine to improve response to therapy). See Acute Pain Syndrome Notes

   2. Assess degree of pain relief every 15–30 minutes; use a pain relief scale to assess response (eg, 0 = none, 1 = little; 2 = moderate; 3 = good; 4 = complete)

3. Time +30 minutes to +2–8 hours after ED arrival

   1. Assess pain relief every 15–30 minutes. If no pain relief achieved, administer one-quarter to one-half of initial loading dose of opioid to relief (see Table 61-1) with coanalgesic (see Acute Pain Syndrome, Notes Section, number 4)

   2. Admit to hospital if complications, treatment ineffective, or oral therapy cannot be maintained

   3. Discharge in absence of above admission criteria on oral analgesics to maintain adequate pain relief and refer to managing clinician

Acute Chest Syndrome

Multicenter Acute Chest Syndrome Study (MACSS) definition: A pulmonary infiltrate consistent with consolidation, plus at least 1 of the following:

• Chest pain

• Fever >38.5°C (>101.3°F)

• Tachypnea

• Wheezing

• Cough

Associated conditions:

• Pulmonary infarction (30%)

• Pulmonary fat embolization (16%)

• Infection (33%) including chlamydia (13%), mycoplasma (12%), viruses (12%), and bacterial isolates (8%) which included Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae

Ballas SK. Semin Hematol 2001;38:307–314

Bellet PS et al. N Engl J Med 1995;333:699–703

Charache A et al. N Engl J Med 1995;332:1317–1322

Emre U et al. J Pediatr 1993;123:272–275

Lacy CF et al., eds. Albuterol. In: Drug Information Handbook 2011. 20th ed. Hudson, OH: Lexi-Comp; 2011:49–51

Rosse WF et al. New views of sickle cell disease pathophysiology and treatment. Hematology Am Soc Hematol Educ Program 2000:2–17

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Vichinsky EP et al. N Engl J Med 2000; 342:1855–1865

Epidemiology

1. Second most common cause of hospitalization in SCD

2. Most common complication of surgery and anesthesia

3. Incidence (per 100 patient-years):

   Hgb SS overall (12.8)

   Hgb SS ages 2–4 years (25.3)

   Hgb SS adults (8.8)

   Hgb Sβ-thalassemia (9.4)

   Hgb SC (5.2)

   Hgb Sβ⁺ thalassemia (3.9)

4. In-hospital mortality:

   9% for adults

   <2% for children

Treatment

Carefully monitor oxygenation, hydration, and acid–base balance. Obtain daily weight, input/output, CBC, and appropriate serum chemistry panels. Measure baseline and pre-/posttransfusion Hgb S concentration. Follow CXR until stabilization is documented

Therapy:

1. Oxygen, by nasal cannula at a rate of 2 L/min or greater if needed to maintain a PaO₂ of 70–80 mm Hg (or oxygen saturation of ≥90%)

2. Hydration with 5% dextrose injection (D5W) or 5% dextrose/0.2% sodium chloride injection (D5W/1⁄4NS) at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions); also refer to Acute Pain Syndrome, Notes Section

3. Bronchodilator therapy for adults exacerbation of asthma (acute, severe):

   1. Albuterol nebulizer solution (5 mg/mL), administer 2.5–5 mg by nebulizer every 20 minutes up to 3 doses, followed by 2.5–10 mg every 1–4 hours as needed or 10–15 mg/hour by continuous nebulization. (For adults with bronchospasm, albuterol nebulizer solution [5 mg/mL], administer 2.5 mg 3–4 times daily as needed)

   2. Albuterol metered-dose inhaler (90 mcg/puff), administer 4–8 puffs every 20 minutes for up to 4 hours, then every 1–4 hours as needed. (For adults with bronchospasm, 2 puffs every 4–6 hours for quick relief)

4. Institute opioids or other analgesic therapy to prevent hypoventilation (see the Acute Pain Syndrome section)

5. Incentive spirometry protocol to prevent hypoventilation in patients able to perform it

6. Transfuse packed RBCs to achieve a Hgb S concentration <30–40%, or to a stable Hgb of 8–9 g/dL (see the section Red Blood Cell Transfusion)

Indications:

• Poor respiratory function

• PaO₂ <70 mm Hg on room air

• A decline in PaO₂ >10% from baseline in a patient with chronic hypoxia

Note: Exchange transfusion should be undertaken in patients with a high baseline Hgb in whom transfusion of RBCs is recommended (eg, goal to reduce the Hct to <30%), signs of increasing infiltrate on CXR, if the arterial PO₂ cannot be maintained above 70 Torr or if the patient is experiencing dyspnea or tachypnea (also see the section Red Blood Cell Transfusion)

Antibiotics should be given to febrile or severely ill patients. This should include:

A third-generation cephalosporin:

Ceftriaxone 1000 mg (maximum, 2000 mg); administer intravenously in 50–100 mL 5% dextrose injection (D5W) over 30 minutes every 24 hours, and

A broad-spectrum macrolide or fluoroquinolone antibiotic:

Azithromycin 500 mg; administer intravenously in 250–500 mL D5W over 60 minutes every 24 hours, or

Ciprofloxacin 400 mg; administer intravenously in 200 mL D5W over 60 minutes every 12 hours

Notes

1. Assess baseline oxygenation and continue to monitor ABGs as needed. The A-a gradient appears to be the best predictor of clinical severity

2. Limit hydration. Avoid fluid overload

3. Incentive spirometry is encouraged since it reduces the risk of ACS by 88% in patients hospitalized with thoracic bone ischemia/infarction

4. In 2010, a Cochrane Collaboration study was performed to assess the benefits and risks associated with the use of bronchodilators in sickle cell disease patients with acute chest syndrome. This study found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. The authors' conclusions stated "if bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated." Recommendations were proposed for well-designed, adequately powered randomized controlled trials to assess the risk and benefits of this treatment in patients with SSD acute chest syndrome. (Knight-Madden JM, Hambleton IR. Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease (review). Cochrane Database Syst Rev 2010 Jul 11;CD003733. Available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003733.pub2/abstract [accessed August 5, 2013])

5. Goal of transfusion therapy is to prevent progression of acute chest syndrome (ACS) to acute respiratory failure. Transfusions may not be required if the decline in A-a gradient is due to chest wall splinting that corrects with adequate analgesic therapy and incentive spirometry

6. Infection is a contributing factor as cause of death in 56% of ACS patients. Organisms include Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, legionella, Staphylococcus aureus, cytomegalovirus, and chlamydia as well as atypical microorganisms (eg, Chlamydia pneumoniae, Mycoplasma pneumoniae)

7. In ACS patients it is often difficult to exclude a bacterial superinfection from a lung infarct

Acute Cholecystitis

Gilbert DN et al., eds. Gallbladder (cholecystitis). In: The Sanford Guide To Antimicrobial Therapy 2011, 41st ed. Speeryville, VA: Antimicrobial Therapy, Inc.; 2011:15

Nzeh DA et al. Pediatr Radiol 1989;19:290–292

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Walker TM et al. J Pediatr 2000;135:80–85

Epidemiology

1. Cholelithiasis occurs as early as 2–4 years of age; incidence progressively increases with age; ≈30% of 18-year-old patients have cholelithiasis

2. Acute attacks of cholecystitis are difficult to differentiate from hepatic crisis. Biliary scintigraphy may be helpful in differentiating acute cholecystitis from sickle hepatic crisis but is not always diagnostic (D'Alonzo WA Jr, Heyman S. Pediatr Radiol 1985;15:395–398)

3. The natural history of asymptomatic cholelithiasis is unknown; however, up to 30% of patients may develop symptoms or complications within 3 years. The prevalence of cholelithiasis appears to be lower in patients co-inheriting α-or β-thalassemia

4. Patients with sickle cell trait have no increased risk of developing pigment stones

Treatment

The treatment of acute cholecystitis is similar to that of the general population

Therapy:

Hydration (as clinically indicated) with 5% dextrose injection (D5W) or 5% dextrose/0.2% sodium chloride injection (D5W/1⁄4NS) at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions). Also, refer to Acute Pain Syndrome, Notes Section

1. Institute opioids or other analgesic therapy as appropriate based on clinical symptoms with superimposed vasoocclusive crises (see the section Acute Pain Syndrome)

2. Antimicrobial therapy including

   Piperacillin sodium 3000 mg + tazobactam sodium 375 mg; administer intravenously in 50–150 mL D5W or 0.9% sodium chloride injection (0.9% NS) over 20–30 minutes every 6 hours, or

   Imipenem 500 mg/cilastatin 500 mg; administer intravenously in 50–100 mL D5W or 0.9% NS over 20–60 minutes every 6 hours (if life-threatening)

3. Elective cholecystectomy is recommended several weeks after an acute episode subsides, given the greater operative risks during an episode of acute cholecystitis in SCD

Note:

• Although cholecystectomy in asymptomatic patients is controversial, an aggressive surgical approach has the benefit of reducing the risk of complications arising from cholecystitis and eliminating the gallbladder as a confounding diagnosis in RUQ pain (eg, sickle cell hepatic crises)

• Laparoscopic cholecystectomy on an elective basis in a well-prepared patient has been reported to be the standard surgical approach to symptomatic patients but does not reduce the risk of sickle cell-related complications as compared with open cholecystectomy

Acute Hepatic Sequestration (Right Upper Quadrant Syndrome)

Characterized by:

1. RUQ pain simulating acute cholecystitis

2. Fever

3. Jaundice

4. Elevations in hepatic transaminases

5. Marked elevations in serum bilirubin/alkaline phosphatase

6. Progressive hepatomegaly

Note: The rapid decrease in transaminases with treatment differentiates hepatic crisis from the slower decline characteristic of acute viral hepatitis

Halton CS. Hepatic sequestration in sickle cell disease. BMJ 1985;290(6740):744

Rosse WF et al. New views of sickle cell disease: pathophysiology and treatment. Hematology Am Soc Hematol Educ Program. 2000:2–17

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Epidemiology

1. A rarely recognized complication of vaso-occlusive crisis in SCD

2. Prevalence in SCD is not well described

3. Approximately 10% of Hgb SS patients develop a transient and less-severe form of intrahepatic cholestasis that is usually self-limited

Treatment

Carefully monitor oxygenation, hydration, and acid–base balance. Obtain daily weight, input/output, CBC, and appropriate serum chemistry panels. Measure baseline and pre-/posttransfusion Hgb S concentration

1. Hydration with 5% dextrose injection (D5W) or 5% dextrose/0.2% sodium chloride injection (D5W/1⁄4NS) at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions)

   Note: In the event of hypervolemia, the administration of diuretic therapy may be required. Also, refer to Acute Pain Syndrome, Notes Section

2. Oxygen by nasal cannula at a rate of 2 L/min or greater, if needed to maintain a PaO₂ of 70–80 mm Hg

3. Institute opioids or other analgesic therapy based on clinical symptoms (see the section Acute Pain Syndrome)

4. Transfuse packed RBCs to maintain Hgb close to baseline and Hgb S <30%

Note:

1. Exchange transfusion is the preferred method of transfusion although simple transfusion may be considered

2. Fatal hyperviscosity syndrome may result from simple transfusion as an episode of hepatic sequestration resolves. A spontaneous and rapid increase in the serum hemoglobin from sequestered RBCs ("reverse sequestration") accounts for this clinical finding. Patients should be carefully monitored in the recovery phase of acute hepatic sequestration for an acutely rising Hgb that could place the patient at risk for hyperviscosity. If suspected, promptly institute exchange transfusion with a goal of reducing the Hct to <30% (also see the section Acute Splenic Sequestration: Hyperviscosity)

Notes

1. Differential diagnosis of RUQ syndrome in a patient with a sickle cell disease who presents with RUQ pain and abnormal LFTs includes: Acute cholecystitis, intrahepatic cholestasis, acute viral hepatitis, biloma, focal nodular hyperplasia in children, fungal ball, hepatic artery stenosis, hepatic infarct/abscess, hepatic vein thrombosis, mesenteric/colonic ischemia, pancreatitis, periappendiceal abscess, pericolonic abscess, pulmonary infarct/abscess, renal vein thrombosis

2. Patients should be taught to regularly monitor their liver size (and spleen size, especially in younger children and in adults coinheriting α-thalassemia who are at risk for acute splenic sequestration) in an effort to identify acute hepatic sequestration in its early stages

Acute Splenic Sequestration

1. Acutely enlarging spleen

2. Decrease in steady state Hgb concentration by at least 2 g/dL and evidence of increased erythropoiesis (eg, marked elevations in the reticulocyte count or nucleated RBCs)

3. In more severe episodes, hypovolemic shock may complicate precipitous drops in Hgb with marked splenic enlargement

Glader BE. Anemia. In: Embury SH et al., eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York, NY: Raven Press; 1994:545–554

Rosse WF et al. New views of sickle cell disease: pathophysiology and treatment. Hematology Am Soc Hematol Educ Program. 2000:2–17

Solanki DL et al. Am J Med 1986;80:985–990

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Epidemiology

1. Majority of cases occur in children with Hgb SS before 2 years of age with almost all by age 6 years

2. Attacks may be associated with or preceded by bacterial or viral infections

3. Acute chest syndrome has been reported to complicate acute splenic syndrome in 20% of cases

4. Occurs less frequently in Hgb SC and Hgb S β⁺-thalassemia disease, but may occur beyond childhood because of persistent splenomegaly

5. Occurrence in adults is rare, but may occur with persistent splenic function in patients with concurrent α-thalassemia

6. A mortality rate of 12% has been reported with first attacks in SCD-SS (Hgb SS)

7. Recurrent episodes may occur in 50% with a mortality rate of 20%

Treatment

Acute management:

Carefully monitor oxygenation, hydration, and acid–base balance. Obtain daily weight, input/output, CBC, and appropriate serum chemistry panels. Measure baseline and pre-/posttransfusion Hgb S concentration

Immediate treatment:

1. Oxygen by nasal cannula at a rate of 2 L/min or higher, if needed to maintain a PaO₂ of 70–80 mm Hg or oxygen saturation ≥90%

2. Hydration with 5% dextrose injection (D5W) or 5% dextrose/0.2% sodium chloride injection (D5W/1⁄4NS) at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions). Also, refer to Acute Pain Syndrome, Notes Section

3. Transfuse packed RBCs by simple transfusion to maintain the baseline Hgb level

Following transfusion therapy and correction of hypovolemia, remobilization of sequestered RBCs may result in a Hgb increase greater than that predicted on the basis of the volume of administered RBCs. Because this can lead to hypervolemia, careful monitoring is indicated and use of diuretic therapy may be required

If hyperviscosity is contributing an important role in the pathogenesis of an acute complication of SCD, exchange transfusion using a mechanical device directed at reducing the hyperviscosity should be performed. The goal of this therapy would be to reduce the Hct to <30%

Chronic management:

Following an acute episode, subsequent management is influenced by the high recurrence rate of this syndrome

1. Chronic transfusions are recommended in children <2 years of age following a severe episode to keep Hgb SS levels <30% until splenectomy can be considered after 2 years of age

2. Splenectomy is recommended in patients who experience a life-threatening episode of acute splenic sequestration shortly after being placed on a chronic transfusion program. A splenectomy can also be considered in patients with chronic hypersplenism

Priapism

Sustained, painful, and unwanted erection resulting from vasoocclusive obstruction of penile venous drainage. Priapism has been classified as:

• Prolonged (>3 hours)

• Stuttering (>few minutes, <3 hours)

Mantadakis E et al. Blood 2000;95:78–82

Rackoff WR et al. J Pediatr 1992;120:882–885

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Winter CC. J Urol 1978;119:227–228

Epidemiology

1. Mean age of onset: 12 years

2. By age 20 years, 89% of males will have experienced 1 or more episodes

3. Precipitating factors include:

   • Trauma

   • Infection

   • Drug use (eg, ethanol, cocaine, sildenafil, testosterone)

   • Prolonged sexual activity

   • Full bladder with infrequent urination

4. Complications include fibrosis of the penis and impotence

Treatment

Outpatient management:

1. Encourage oral fluid intake

2. Administer oral analgesics

3. Attempt to urinate as soon as priapism develops and encourage frequent urination

Instituting medication and conservative therapy within 4–6 hours of the onset of symptoms can usually lead to reduction of erection

In-patient management:

Carefully monitor oxygenation, hydration, and acid–base balance. Obtain daily weight, input/output, CBC, and appropriate serum chemistry panels, and baseline coagulation profile. Measure baseline and pre-/posttransfusion Hgb S concentration

1. Hydration with 5% dextrose injection (D5W) or 5% dextrose/0.2% sodium chloride injection (D5W/1⁄4NS) at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions). See Acute Pain Syndrome, Notes Section

2. Oxygen by nasal cannula at a rate of 2 L/min or greater if needed to maintain a PaO₂ of 70–80 mm Hg or oxygen saturation ≥90%

3. Institute opioids or other analgesic therapy as appropriate (see the section Acute Pain Syndrome)

4. An urologist can perform penile aspiration if more conservative measures fail to achieve detumescence within 1 hour. Use a 23-gauge needle to aspirate blood from the corpus cavernosum followed by irrigation with a 1:1,000,000 solution of epinephrine in 0.9%sodium chloride injection

   Note: This is performed within 4–6 hours of onset and under conscious sedation and local analgesia. Successful in 15 young males on 37 of 39 occasions (Mantadakis E et al. Blood 2000;95:78–82)

5. Transfusion of packed RBCs is considered if penile aspiration with irrigation fails to achieve detumescence. Administer packed RBCs to reduce Hgb S to <30%

   Note: It is unclear if simple transfusion is equivalent to exchange transfusion

Management of recurrent priapism:

1. Chronic simple transfusion programs have been utilized to maintain the Hgb S <30%

   Note: Limit this approach to 6–12 months with frequent assessments

2. Penile shunting (Winter procedure) creates a shunt between the glans penis and the distal corpora with a Tru-Cut biopsy needle. This permits penile blood to drain from the distended corpora cavernosa into the uninvolved corpus spongiosa

   Note: Complications of priapism and its treatment:

   • Bleeding from the holes placed in the penis as part of the penile aspiration or shunting procedures

   • Infection, skin necrosis, damage, or strictures of the urethra, fistulas, and impotence

Transient Red Cell Aplasia (TRCA)

Characterized by a temporary suppression of erythropoiesis. Presenting manifestations may include:

• Preceding febrile illness

• Headache

• Fatigue

• Dyspnea

• More severe anemia than usual

• Reticulocytopenia^✫ (eg, <1%)

Anand A et al. N Engl J Med 1987;316:183–186

Bell LM et al. N Engl J Med 1989;321:485–491

Gilbert DN et al., eds. Parvo B19 virus (erythrovirus B19). In: The Sanford Guide to Antimicrobial Therapy 2011, 41st ed. Speeryville, VA: Antimicrobial Therapy; 2011:156

Kurtzman G et al. N Engl J Med 1989;321:519–523

Ohene-Frempong K, Steinberg MH. Clinical aspects of sickle cell anemia in adults and children. In: Steinberg MH et al., eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. New York, NY: Cambridge University Press; 2001:611–670

Serjeant GR et al. Lancet 1993;341:1237–1240

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Young NS, Brown KE. N Engl J Med 2004;350:586–597

Epidemiology

In regions not endemic for malaria, 70–100% of episodes are caused by human parvovirus B19

Treatment

Transfuse packed RBCs to maintain Hgb close to baseline if ≥25% decrease in Hgb from baseline with declining or absent reticulocyte levels and symptomatic anemia

Transfuse small volumes cautiously to avoid hypervolemia and complications arising from an abrupt increase in serum viscosity

Notes:

1. Although TRCA is usually self-limited with resolution over a period of 2–3 weeks, transfusion support may be required to maintain the RBC mass and blood volume during this time period

2. If patients are beginning to show evidence of RBC production as determined by reticulocyte count, transfusion support may not be required

3. During the earliest phases of acute illness, obtain anti-B19 parvovirus IgM and IgG levels. If initial titers are negative, repeat in 1 week to assess for recent infection manifested by a rise in IgM levels

   Obtaining B19 parvovirus PCR (polymerase chain reaction) may be better for documenting acute infection

4. If there is failure to spontaneously resolve the B19 infection, discontinuing immunosuppressive therapy (if applicable) or instituting antiretroviral therapy in patients with HIV infection (if applicable) may terminate the underlying B19 viremia

5. In patients with persistent chronic B19 viremia and anemia requiring ongoing transfusion support, intravenous immunoglobulin containing viral neutralizing antibody may lead to a prompt decline in serum viral B19 viral DNA and accompanying reticulocytosis and increased Hgb production

Immune globulin intravenous (human) 400 mg/kg per day, intravenously, daily for 5 consecutive days, days 1–5 (total dosage/5-day course = 2000 mg/kg) or 1000 mg/kg IV for 3 consecutive days

Occasional responses to a single 400–mg/kg dose have been reported

Notes

1. Siblings and close contacts with SCD should be monitored for the development of aplastic crises

2. Complications reported to arise from TRCA in small series or single centers include bone marrow necrosis with pancytopenia, stroke, acute chest syndrome, splenic or hepatic sequestration, and glomerulonephritis

3. Most adults have acquired immunity to B19 parvovirus; however, susceptible individuals exposed to patients with active B19 parvovirus infection are at risk of contracting erythema infectiosum. Isolation precautions for pregnant staff are necessary

Stroke and CNS Disease

Cerebrovascular accidents (CVAs), transient ischemic attacks (TIAs), subarachnoid, intraparenchymal, and intraventricular hemorrhage

Broderick JP et al. Stroke 1999;30:905–915

Lansberg MG et al. Chest 2012;141(2_Suppl): e601S–e636S. doi:10.1378/chest.11–2302

Malinow MR et al. Circulation 1999;99:178–182

Mayberg MR et al. Stroke 1994;25:231–232

Ohene-Frempong K et al. Blood 1998;91:288–294

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002:83–94

Notes

• Without controlled trials in adults with SCD documenting the worth of transcranial Doppler (TCD) in reducing the risk of brain infarction, prevention should be based on standard recommendations applicable to adults without SCD

• In adults with SCD, the role of chronic transfusion in the prevention and treatment of stroke is unclear. However, chronic transfusion with the target of reducing Hgb S to less than 30% of total hemoglobin, as used in children, is an option. Moreover, the duration of time after which transfusion can be safely stopped has not been defined though some have suggested that transfusion may be safely withdrawn in older patients who have been extensively treated (Rana S et al. J Pediatr 1997;131:757–760). Management of iron overload must be managed with chelation

• In the event of intracranial hemorrhage complicating SCD in adults, consultation with a neurological specialty team is also indicated with stabilization in a neurological intensive care unit. A careful evaluation to rule out meningitis, sepsis, hypoxia, drug intoxication, or other metabolic arrangements is required (recommendations from children with SCD). A noncontrast cranial CT should be performed as soon as possible. The work-up and management should be approached based on the location of the blood on CT scan (eg, SAH, intraparenchymal hemorrhage, intraventricular hemorrhage). Initial management should include: IV normotonic fluids to avoid dehydration; a rapid search for coagulopathy (eg, PT, aPTT); complete blood count, comprehensive metabolic profile, Hgb S level; discontinuation of any medication with hemorrhagic risk and correction of any coagulopathy. A neurosurgical consultation should be obtained to advise for additional diagnostic studies and management as needed to identify aneurysms, arteriovenous malformations or hematoma that may require surgical intervention. The effect of transfusion on the course and outcome of intracranial hemorrhage complicating SCD is not know; however, reducing the Hgb S to <30% of total Hgb is recommended

Treatment

Compared with children, there is little information on the treatment and prevention of stroke in adults with SCD. Treatment and prevention recommendations for adults with SCD are therefore based primarily on current recommendations in adults without SCD. It is recommended that physicians with experience and skill in stroke management and interpretation of CT scans supervise treatment

General guidelines:

1. Oxygen by nasal cannula at a rate of 2 L/min or greater if needed to maintain a PaO₂ of 70–80 mm Hg for oxygen saturation of ≥90%

2. Assess the patient for cause of pain and complications. Conduct a rapid pain assessment with a simple self-reported pain scale. Institute opioids or other analgesic therapy as appropriate (see Acute Pain Syndrome)

3. Hydration (if required based on clinical evaluation to avoid dehydration) with normotonic fluids: eg, 5% dextrose solution (D5W)/normal saline (NS)

TIAS and CVAs:

Consult the Feburary 2012:141 (2 Suppl) Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Physicians Evidence-Based Clinical Guidelines section on Antithrombotic and Thrombolytic Therapy for Ischemic Stroke. Specifics on inclusion/exclusion criteria for recombinant tissue plasminogen activator (r-TPA) as well as additional antithrombotic management recommendations for ischemic stroke/TIA and guidance in patients with a history of symptomatic primary intracerebral hemorrhage are expertly presented in this guideline

Subarachnoid Hemorrhage (SAH):

1. Transfuse packed RBCs to reduce Hgb S to <30%

   Note: The effect of RBC transfusion on altering the course or outcome of SAH is unknown

2. Nimodipine (calcium channel antagonist) is indicated in adults with SAH from ruptured berry aneurysms to counteract delayed arterial vasospasm

Dosage: administer 60 mg orally every 4 hours for 21 days (one hour before or two hours after a meal; avoid grapefruit juice). Nimodipine may increase the blood pressure lowering effect of concomitantly administered antihypertensives and blood pressure should be carefully monitored; dose adjustment of the blood pressure lowering drug(s) may be necessary. Nursing mothers are advised not to breast feed their babies when taking nimodipine. Dosage should be reduced to one 30 mg capsule every 4 hours with close monitoring of blood pressure in patients with "severely disturbed liver function" (eg, liver cirrhosis). Strong inhibitors of CYP3A4 should not be administered concomitantly with nimodipine

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]. (See chapter 13 on stroke and CNS disease in adults)

Work-up for Adults with TIA or Ischemic Stroke

CBC/diff; EKG; transthoracic echocardiogram with consideration given to TEE, especially in young patients; aPTT; PT; and a brain study to include MRI, DWI, and MRA, and/or TCD, and carotid duplex US or CT angiography to determine the status of the intracranial and extracranial vessels. Blood tests for protein C and S deficiency, homocysteine elevation, and anticardiolipin antibodies may be appropriate. Health care providers should consider etiologies seen in young patients with stroke without SCD: eg, CNS infection, illicit drug use and arterial dissection

Epidemiology

Cerebrovascular accidents (CVAs) are a leading cause of death in children and adults

Age-adjusted prevalence for CVAs:

• Hgb SS (4.01%)

• Hgb Sβ-thalassemia (2.43%)

• Hgb Sβ⁺ thalassemia (1.29%)

• Hgb SC (0.84%)

Among Hgb SS patients first CVAs were:

• Infarctive (53.9%)

• Hemorrhagic (34.2%)

• TIA (10.5%)

• Both infarctive/hemorrhagic (1.3%)

In all SCD patients recurrent CVAs occur in 16% of survivors of first-time CVAs

Overall, the mortality rate for hemorrhagic CVA was 24–26% for Hgb SS patients

Adapted from The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Notes:

• r-tPA should not be given unless emergent care and appropriate treatment facilities available

• Antiplatelet agents are usually recommended for TIA in TIA's without SCD, but there are few data on the efficacy in SCD

• If antiplatelet therapy is administered in patients with acute ischemic stroke or TIA (after intracranial hemorrhage has been excluded), aspirin therapy at a dosage of 160–325 mg should be administered orally within 48 hours after symptom onset and reduced after 1–2 weeks to secondary prevention dosing (75–100 mg/day orally). Benefits: (1) fewer deaths: 9 per 1000; (2) good functional outcome at 30 days after ischemic stroke: 7 per 1000; (3) reduction in recurrent strokes: 7 per 1000. Risks: (1) nonfatal major extracranial bleeding events: 4 per 1000; (2) symptomatic intracranial hemorrhages: 2 per 1000

• Aspirin therapy for acute ischemic stroke or TIA should not be given for the first 24 hours after administration of r-tPA

According to established guidelines, alteplase (t-PA) is indicated when:

• The patient is at least 18 years old

• The patient's NIH Stroke Scale score is ≥4 (ischemic stroke in any circulation with a clinically significant deficit)

• Alteplase can begin within 3 hours after symptom onset

• Cranial CT shows no evidence of hemorrhage

It is not clear whether alteplase is appropriate for patients with SCD and hyperacute ischemic stroke; no experience with its use has been reported. However, there is no clear justification to exclude SCD patients. Caution is advised if severe stroke (<7% risk of symptomatic brain hemorrhage with an absolute risk of fatal ICH of 3.5% with IV r-tPA initiated within 3 hours in patients with acute ischemic stroke)

The 9th ed ACCP Guidelines on Antithrombotic and Thrombolytic Therapy for Ischemic Stroke (See reference by Lansberg MG et al. Chest 2012;141(2_Suppl): e601S–e636S. doi:10.1378/chest.11-2302) also recommends r-tPA use "in patients with acute ischemic stroke in whom treatment can be initiated within 4.5 hours but not within 3 hours of symptom onset"

Thrombolytic therapy cannot be recommended if:

• Evidence of intracranial hemorrhage (ICH) on pretreatment evaluation

• Suspicion of subarachnoid hemorrhage (SAH) on pretreatment evaluation

• Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma or previous stroke

• History of ICH

• Minor neurological deficit

• Rapidly improving symptoms

• Uncontrolled hypertension at the time of treatment (eg, >185 mm Hg systolic or >110 mm Hg diastolic)

• Seizure at the onset of stroke

• Active internal bleeding

• Intracranial neoplasm, arteriovenous malformation, or aneurysm

• Known bleeding diathesis, including but not limited to: Current use of oral anticoagulants (eg, warfarin sodium) or an INR >1.7 or a PT >15 seconds

  Administration of heparin within 48 hours preceding the onset of stroke and have an elevated aPTT at presentation

  Platelet count <100,000/mm³

• Blood glucose of <50 mg/dL or >400 mg/dL

Chronic Pain Syndrome: Acute Osteomyelitis and Acute Septic Arthritis

Almeida A, Roberts I. Br J Haematol 2005;129:482–490

Gilbert DN et al., eds. Bone: osteomyelitis. In: The Sanford Guide to Antimicrobial Therapy 2011. 41st ed. Speeryville, VA: Antimicrobial Therapy; 2011:4

Glader BE. Anemia. In: Embury SH et al., eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York, NY: Raven Press; 1994:545–554

Keeley K, Buchanan GR. J Pediatr 1982;101:170–175

Rao S et al. J Pediatr 1985;107:685–688

Sickle cell disease: Clinical and epidemiologic aspects. In: Bunn HF, Forget BG, eds. Hemoglobin: Molecular, Genetic and Clinical Aspects. Philadelphia, PA: WB Saunders; 1986:502–564

Solanki DL et al. Am J Med 1986;80:985–990

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Epidemiology

United States and most of the world:

Salmonella sp. are the most common causative organisms of osteomyelitis in Hgb SS patients (~60% or higher); Staphylococcus aureus is second most common, followed by Gram-negative enteric bacilli

Some regions of the world:

Gram-negative organisms, such as Klebsiella sp. may predominate

Treatment

1. Assess the patient for cause of pain and complications. Rapid pain assessment with simple self-reported pain scale

2. Hydration (as appropriate to the patient's clinical evaluation) with 5% dextrose injection or 0.9% sodium chloride injection at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions); Also, refer to Acute Pain Syndrome, Notes Section

3. Institute opioid therapy or other analgesics as appropriate (see the section Acute Pain Syndrome)

4. Institute appropriate antibiotics (see below)

Adults with Acute Osteomyelitis

Empiric parenteral antibiotics that cover Salmonella sp., Staphylococcus aureus, and other Gram-negative organisms until culture results are available, for example:

Vancomycin 1000 mg; administer intravenously over 1 hour every 12 hours, with

Ciprofloxacin 400 mg; administer intravenously over 1 hour every 12 hours, or

Levofloxacin 750 mg; administer intravenously over 90 minutes every 24 hours

Note:

• Collect blood and bone cultures before empiric therapy

• If blood culture is negative, need culture of bone; culture of sinus tract not predictive of bone culture

• Definitive treatment is chosen according to in vitro susceptibility and continued for up to 6 weeks, depending on the nature and extent of the infection

• For the patient with suspected vertebral osteomyelitis ± epidural abscess, obtain MRI early to look for epidural abscess

• The doses identified are for adults with clinically severe (often life-threatening) infections and assume normal renal function and not severe hepatic dysfunction

Adults with Acute Monoarticular Septic Arthritis (Not at Risk for Sexually Transmitted Disease)

Empiric parenteral antibiotics (after collection of blood and joint fluid) that covers Salmonella sp., Staphylococcus aureus, and other Gram (−) organisms until culture results are available (see empiric antimicrobial coverage in section on Acute Osteomyelitis)

Note: Consider surgical drainage of the joint with the evacuation of exudates and breaking up joint loculations to reduce the risk of persistent infection and articular cartilage destruction

Notes

1. Osteomyelitis in SCD must be differentiated from acute bone infarction. Plain radiography and radionuclide bone imaging are of little or no use in differential diagnosis. However, radionuclide marrow imaging may be useful in depicting diminished uptake in infarction and normal uptake in infection

2. Despite progress made with various imaging techniques, a definitive diagnosis of osteomyelitis in SCD depends more upon clinical assessment and positive blood or bone cultures obtained by aspiration or biopsy

3. Consult institutional antimicrobial susceptibility profiles to guide selection of fluoroquinolone (in particular)

Systemic Fat Embolization

Characterized by embolization of necrotic marrow and fat in the setting of massive bone marrow infarction. Respiratory insufficiency and multiorgan failure from systemic emboli may occur with clinical signs dependent upon the organ involved and degree of involvement

Castro O. Hematol Oncol Clin North Am 1996;10:1289–1303

Milner PF, Brown M. Blood 1982;60:1411–1419

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Vichinsky EP et al. N Engl J Med 2000;342:1855–1865

Epidemiology

1. A well-documented complication in the setting of acute chest syndrome

2. Responsible for symptoms in 8.8% of patients with acute chest syndrome

3. Systemic fat embolization can occur concurrently with an infectious agent

4. Risk factors:

   Hgb SC

   Pregnancy

   Prior corticosteroid treatment

Treatment

A high index of suspicion is required. All ACS patients are considered to be at risk. Treatment should not await proof of diagnosis

1. Oxygen by nasal cannula at a rate of 2 L/min, or greater if needed to maintain a PaO₂ of 70–80 mm Hg or oxygen saturation ≥90%. If needed, initiate critical care supportive measures to manage respiratory insufficiency

2. Assess the patient for cause of pain and complications. Conduct a rapid pain assessment with a simple self-reported pain scale. Institute opioids therapy or other analgesics based upon an individual patient's clinical evaluation (see the section Acute Pain Syndrome)

3. Hydration with 5% dextrose injection or 5% dextrose/0.2% sodium chloride injection at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions). Also, refer to Acute Pain Syndrome, Notes Section

4. Transfuse packed RBCs to reduce Hgb S to <30%

Note: Case reports suggest that exchange transfusion may prevent some deterioration (see sections on Acute Chest Syndrome and Red Blood Cell Transfusion)

Notes

1. Clinical symptoms may include severe bone pain, fever, hypoxia, azotemia, liver damage, altered mental status or coma, progressive anemia and thrombocytopenia, and disseminated intravascular coagulation

2. Findings that prove systemic fat embolization: Fat droplets within retinal vessels or in biopsies of petechiae

3. Indirect evidence of systemic fat embolization: Positive fat stains in bronchial macrophages, lung microvesicle cells, or venous blood buffy coat

4. In the setting of acute chest syndrome patients with systemic fat embolization have a lower oxygen saturation at presentation, are more likely to have upper lobe infiltrates during hospitalization, and have a higher incidence of vasoocclusive events in comparison with patients with pulmonary infarction or infection

5. Systemic fat embolization may precipitate or coexist with acute chest pain syndrome (see treatment section for Acute Chest Syndrome)

Vichinsky EP et al. N Engl J Med 2000;342:1855–1865

Acute Multiorgan Failure Syndrome

Sudden onset of severe dysfunction of 2 or more major organ systems during an acute painful vasoocclusive episode. This syndrome may occur without an apparent predisposing event other than high baseline hemoglobin

Initial presentation:

  Fever

  Nonfocal encephalopathy

  Evidence of rhabdomyolysis

  Rapid decrease in Hgb and platelet count

Organ-specific manifestations:

  Renal: hematuria or acute renal failure

  Liver: acute hepatic necrosis or hepatic sequestration syndrome

  Lung: pulmonary infiltrates, hypoxia

  Bone marrow: generalized necrosis with fat emboli

  Pancreas: pancreatitis

Notes:

1. For associated acute chest syndrome, see the section Acute Chest Syndrome

2. The use of granulocyte colony-stimulating factor has been associated with sickle cell crisis and multiorgan failure in 3 patients with sickle cell syndrome (2 patients after stem-cell mobilization with 1 death; 1 patient with stage II breast cancer treated with CMF chemotherapy + G-CSF)

Abboud M et al. Lancet 1998;351:959

Adler BK et al. Blood 2001;97:3313–3314

Bakanay SM et al. Blood 2005;105:545–547

Hassell KL et al. Am J Med 1994;96:155–162

Rosse WF et al. New views of sickle cell disease: pathophysiology and treatment. Hematology Am Soc Hematol Educ Program. 2000:2–17

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Wei A, Grigg A. Blood 2001;97:3998–3999

Epidemiology

1. This syndrome is most commonly reported in Hgb S β-thalassemia but may occur in patients with classical Hgb SS disease with a high hematocrit

2. Second only to acute chest syndrome as the cause of sickle cell–related mortality

Treatment

Carefully monitor oxygenation, hydration, and acid–base balance. Obtain daily weight, input/output, CBC, and appropriate serum chemistry panels. Measure baseline and pre-/post-transfusion Hgb S concentration. Follow CXR until stabilization is documented

1. Oxygen by nasal cannula at a rate of 2 L/min, or greater if needed to maintain a PaO₂ of 70–80 mm Hg. Mechanical ventilation as appropriate to the clinical condition

2. Hydration with 5% dextrose injection or 5% dextrose/0.2% sodium chloride injection at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions) with careful assessment of hydration status and fluid requirements in the setting of concomitant acute renal failure

3. Assess the patient for cause of pain and complications. Rapid pain assessment with simple self-reported pain scale if possible based on the underlying mental status. Institute opioids therapy or other analgesics as appropriate (see the section Acute Pain Syndrome)

4. Perform aggressive transfusion to reduce Hgb S to <30%:

   Simple transfusion (Packed RBCs) if Hgb <7 g/dL and no evidence of hyperviscosity, or

   Exchange transfusion using a mechanical device, if Hgb >7 g/dL or hyperviscosity is playing a role in the pathogenesis of the acute complication of SCD

   Note: Prompt initiation of transfusion therapy or exchange transfusion has the potential of reversing this syndrome

5. Critical care support is directed at the affected underlying organ systems

6. If narcosis is suspected:

   Try Naloxone 0.4 mg (1 mL) in 9 mL 0.9% sodium chloride injection to produce a concentration = 0.04 mg/mL, administer 0.5 mL (0.02 mg) by intravenous injection every 2 minutes, or

   Naloxone 0.4–2 mg/dose; administer intravenously, subcutaneously, or intramuscularly; may repeat every 2–3 minutes as needed to a maximum dose of 10 mg

7. Empiric antibiotics, pending culture results

   Antibiotics should be given to febrile or severely ill patients. These include (normal renal function):

   A third-generation cephalosporin:

   Ceftriaxone 1000 mg (maximum 2000 mg); administer intravenously in 50–100 mL D5W over 30 minutes every 24 hours, and

   A broad-spectrum macrolide or fluoroquinolone antibiotic:

   Azithromycin 500 mg; administer intravenously over 60 minutes every 24 hours, or

   Ciprofloxacin 400 mg; administer intravenously over 60 minutes every 12 hours

Notes

There are no reported prospective trials in the management of multiorgan failure syndrome complicating SCD. Treatment approaches are based upon clinical observations and expert opinion

Epidemiology

1. Fever is a common presenting symptom in SCD and may represent the first indication of a serious infection and/or underlying SCD-associated clinical syndrome

2. Fever in SCD is presumed to be caused by infection and treated as such until proven otherwise

Clinical Features

1. Adult patients, parents, and children should be taught that a temperature ≥38.5°C (≥101.3°F) is an emergency and advised to seek immediate medical evaluation

2. Risk factors/etiologies for fever in SCD

   1. Functional asplenia

   2. Clinical syndromes associated with SCD: Acute chest syndrome (ACS), transient RBC aplasia, fat embolism, vasoocclusive crisis, sequestration syndromes (hepatic, splenic), acute cholecystitis, viral hepatitis, acute bone infarction, osteomyelitis, septic arthritis, skin ulceration, stroke, intracranial hemorrhage, multiorgan failure syndrome

   3. Drug therapy: Hydroxyurea (febrile neutropenia, drug-induced); allergic reactions to antimicrobial therapy, others; rare cases of ceftriaxone-induced AIHA

   4. Hemolytic transfusion reactions

   5. Infections: B19 parvovirus, HIV, meningitis, otitis media, PID, sinusitis, SBE, STDs, viral hepatitis

Management of Fever

1. Initial focused work-up

   Table Graphic Jump Location

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   Management of Fever

   Assess for localized or systemic infection, pallor, liver/spleen size, neurologic status
   Obtain vital signs, oxygen saturation, assess hemodynamic status of patient
   Sign or Symptom	Clinical Finding in SCD
   Pallor	Aplastic crisis, splenic or hepatic sequestration, other causes for reduced hemoglobin
   Shortness of breath, chest pain, cough, splinting; new heart murmur	Vasoocclusive crisis, ACS, pneumonia, fat embolism; SBE
   Abdominal pain, swelling (may be accompanied by jaundice)	Evaluate for change in size of liver and spleen from baseline that may suggest sequestration; RUQ pain syndrome; cholecystitis, hepatitis
   Dysuria, flank or pelvic pain/fullness, vaginal discharge	UTI, pyelonephritis, PID, pregnancy, STD
   Localized bone or joint pain, erythema, swelling	Marrow ischemia, osteomyelitis, septic arthritis
   Skin redness, ulceration	Leg ulcer, cellulitis
   Neck stiffness, altered MS, headache, focal neurologic signs	Meningitis, acute stroke, intracranial hemorrhage

2. Laboratory assessment

   1. CBC with differential, reticulocyte count (RPI), comprehensive metabolic profile (CMP), urinalysis, blood cultures; throat culture, nasopharyngeal swab as indicated; type and cross-match as indicated, request if available, minor antigen-matched, sickle-negative, leukodepleted RBCs), other cultures as indicated (eg, CSF, bone)

3. Empiric antibiotic use

   1. Administer antibiotics empirically before initial laboratory tests or imaging study results are available

   2. Empirically select antibiotics directed against common bacterial pathogens based on epidemiology and antimicrobial sensitivity (in the United States, most common include: Streptococcus pneumoniae, Salmonella sp., Escherichia coli, Staphylococcus aureus)

   Table Graphic Jump Location

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   Management of Fever

   Pathogens to be Covered by Empiric Therapy

   Clinical Situation	Pathogens to be Covered
   Fever without source (rule-out sepsis)	Streptococcus pneumoniae Haemophilus influenzae type B Consider broadening to cover: Gram (−) enterics, Salmonella
   Meningitis	Streptococcus pneumoniae Haemophilus influenzae type B Consider broadening to include: Neisseria meningitidis
   Acute chest syndrome (ACS)	Streptococcus pneumoniae Mycoplasma pneumoniae Chlamydia pneumoniae Consider broadening to cover: Legionella, RSV
   Osteomyelitis/septic arthritis	Salmonella Staphylococcus aureus Streptococcus pneumoniae
   Urinary tract infection	Escherichia coli Other Gram (−) enterics
   Empiric Antibiotics	Dose, Schedule (Normal Renal Function)
   Ceftriaxone	Administer 1 g; administer intravenously over 30 minutes q24h; 2 g maximum dose and vancomycin
   Vancomycin	Administer 15 mg/kg; administer intravenously over 1 hour q12h

   • Meningitis (bacterial, acute): The goal is empiric therapy; then obtain CSF within 30 minutes. If a focal neurologic deficit is present, give empiric therapy, then head CT, then LP. Primary regimen: Administer ampicillin 2 g intravenously over 30 minutes q4h and ceftriaxone 2 g intravenously over 30 minutes q12h and vancomycin 500–750 mg intravenously over 60 minutes q6h Dexamethasone to block TNF production is administered at 0.15 mg/kg intravenously over 15 minutes q6h for 2–4 days with the first dose 15–20 minutes prior to or concomitant with the first dose of antibiotic (de Gans J, van de Beek D. N Engl J Med 2002;347:1549–1556; Tunkel AR, Scheld WM. N Engl J Med 2002;347:1613–1615)

   • ACS (if present): Add a broad-spectrum macrolide or fluoroquinolone antibiotic (see the section Acute Chest Syndrome)

4. Further evaluation and management

   1. Goal-oriented management for associated SCD syndromes

   2. Review patient's most recent medical evaluation; assess for prior infections, surgical history, medications (current, OTC, recreational), allergies, communicable disease exposure; any changes in CBC/diff, reticulocyte count, CMP from baseline, and any change in size of liver and spleen from baseline

   3. LP for meningitis; joint fluid analysis for effusions; CXR for respiratory signs and symptoms (S×S); x-rays /scans for bone pain

   4. Consider abdominal ultrasound, liver function tests, amylase, and lipase for right upper quadrant pain, epigastric or severe abdominal pain (to rule out cholelithiasis, cholecystitis, pancreatitis)

   5. Orthopedic surgery consultation for aspiration and culture of bone or joint if osteomyelitis or septic arthritis are suspected

   6. Oxygen by nasal cannula or face mask if required to keep oxygen saturation ≥92% or ≥ patient's baseline value if ≥92%

   7. Type and crossmatch and consider RBC transfusion if Hgb is 1–2 g/dL or more below patient's usual baseline, if acute chest syndrome is suspected, or if the patient shows any signs of hemodynamic compromise from anemia

   8. Hydration with 5% dextrose injection (D5W) or 5% dextrose injection with 0.225% sodium chloride (D5W/1⁄4NS) at a rate not to exceed 1.5 times maintenance (volume to include any drug infusions). Note: Increased fluids may be required if the patient is dehydrated or if insensible losses are increased with persistent fever; also refer to Acute Pain Syndrome, Notes Section

   9. Acetaminophen 15 mg/kg PO q4h (maximum daily dose: 75 mg/kg). Ibuprofen may be added at a dose of 10 mg/kg PO q6–8h if no contraindication (eg, coagulopathy, gastritis, ulcer or renal impairment). Limit more frequent dosing to the first 72 hours (maximum)

5. Criteria for hospital admission

   Any of the following:

   1. CXR infiltrate or abnormal oxygen saturation

   2. Hgb <5 g/dL (or ≥2 g/dL decline from baseline)

   3. WBC >30,000/mm³ or <5000/mm³

   4. Platelet count <100,000/mm³

   5. Hemodynamic instability

   6. Presence of identified SCD-associated syndromes

   7. History of sepsis

   8. Signs of meningitis

6. Criteria for hospital discharge

   1. Afebrile ≥24 hours with negative cultures ≥24–48 hours

   2. Able to take adequate fluids and PO medications, if applicable

   3. Resolution of pulmonary signs and symptoms or documentation of adequate room air oxygenation

   4. Stable hemoglobin and hematocrit without evidence of aplastic or sequestration crisis

   5. Appropriate follow-up arranged

CMP, Comprehensive metabolic profile; CT, computerized tomography; D/C, discharge; GU, genitourinary; LP, lumbar puncture; MS, mental status; PID, pelvic inflammatory disease; q, every; RSV, respiratory syncytial virus; SBE, subacute bacterial endocarditis; STD, sexually transmitted disease; S×S, signs and symptoms; TNF, tumor necrosis factor; UTI, urinary tract infection

Notes:

1. The majority of clinical evidence for the management of fever in SCD is derived from children instead of adults

2. Guidelines for empiric antibiotic treatment in adults are similar to guidelines for children unless altered by other identified problems

3. For a discussion on the management of specific SCD syndromes, refer to the sections on Acute Pain Syndrome, Acute Chest Syndrome, RUQ Syndrome, Hepatic Sequestration, Splenic Sequestration, Systemic Fat Embolization, Acute Cholecystitis, Transient RBC Aplasia, Acute Osteomyelitis and Acute Septic Arthritis, or Stroke and CNS Disease

Bernini JC et al. J Pediatr 1995;126(5 Pt 1):813–815

Gilbert DN et al., eds. Central nervous system: meningitis, bacterial, acute. In: The Sanford Guide to Antimicrobial Therapy 2011, 41st ed. Speeryville, VA: Antimicrobial Therapy; 2011:7–8

Hsu L, Adamkiewicz T. Care Path: inpatient management of fever. In: Sickle Cell Information Center Guidelines. Eckman J, Platt A, eds; April 1, 2001. http://scinfo.org/care-paths-and-protocols-children-adolescents/care-path-inpatient-management-of-fever. Accessed August 5, 2013. Sickle Cell Information Center, Georgia Comprehensive Sickle Cell Center at Grady Memorial Health System. The Sickle Cell Foundation of Georgia, Inc. Emory University School of Medicine, Department of Pediatrics, Atlanta, GA, Morehouse School of Medicine

Miller ST et al. J Pediatr 1991;118:30–33

Mountain States Regional Genetic Services Network. Sickle Cell Disease in Children and Adolescents: Diagnosis, Guidelines for Comprehensive Care, and Protocols for Management of acute and Chronic Complication. 2001

Poncz M et al. J Pediatr 1985;107:861–866

Section on Hematology/Oncology Committee on Genetics; American Academy of Pediatrics. Pediatrics 2002;109:526–535

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Wright J et al. J Pediatr 1997;130:394–399

Zarkowsky HS et al. J Pediatr 1986;109:579–585

Regimen: Hydroxyurea

Charache S et al. N Engl J Med 1995;332:1317–1322

Rodgers GP et al. N Engl J Med 1990;322:1037–1045

Steinberg MH. Hematology Am Soc Hematol Educ Program 2000:9–13

Steinberg MH et al. JAMA 2003;289:1645–1651

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002 (chapters 26 and 29). www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Initial dosing

Hydroxyurea 10–15 mg/kg per day (based on actual or ideal body weight, whichever is less); administer orally in a single daily dose for 6–8 weeks (total dosage/week = 70–105 mg/kg)

Maintenance Therapy

Adjust hydroxyurea dosage as outlined in the table of Treatment Modifications

Treatment Modifications

Note: If no major toxicity is observed, escalate hydroxyurea dosage by 5 mg/kg per day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over a 24-week period) or 35 mg/kg per day is reached. In the study, 33% and 51% of patients received maximal doses of hydroxyurea (35 mg/kg per day) at 6 and 21 months, respectively

Notes:

1. A trial period of 6–12 months without transfusion support is adequate provided the patient does not suffer an intercurrent illness that suppresses erythropoiesis

2. Since hydroxyurea is a teratogen and its effects in pregnancy are unknown, contraception should be practiced and pregnancy should be avoided if the patient or their sexual partner is receiving hydroxyurea. Patients should be instructed to notify their physician if they plan to or become pregnant so treatment can be D/C'd

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

The Multicenter Study of Hydroxyurea for Sickle Cell Anemia (MHS Study), a landmark prospective, double-blind, placebo-controlled, dose-escalation trial evaluated the effect of hydroxyurea on the frequency of painful vasoocclusive crises in adults with sickle cell disease and ≥3 painful crises/year. The MSH Study established hydroxyurea as the first clinically acceptable drug to prevent painful crises in adults with sickle cell anemia. Among 148 males and 151 females enrolled, 75% of patients took 80% of their capsules

Hydroxyurea has been recommended in the following settings (Management of SCD. In: The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013])

1. Adults (FDA-approved indication), adolescents or children with Hgb SS after consultation with parents (children, adolescents) and physician

2. Hgb Sβ-thalassemia and frequent pain episodes

3. History of acute chest syndrome, other severe vaso occlusive events or severe symptomatic anemia

Efficacy

• Median rates of vasoocclusive crises were reduced by 44% with hydroxyurea

• There were no differences between the 2 arms in the rates of death, stroke, chronic transfusion, or hepatic sequestration

Treatment Modifications

Toxicity

Charache S et al. N Engl J Med 1995;332:1317–1322

Steinberg MH et al. JAMA 2003;289:1645–1651

1. Almost all patients had treatment temporarily stopped because of myelosuppression with counts usually recovering within 2 weeks

2. Leukemia has been reported in 4 adults with SCD treated with hydroxyurea from individual case reports and a single observational study (Lanzkron S et al. In: Hydroxyurea treatment for SCD. NIH Consensus Conference Feb 25–27, 2008:47–49a) http://consensus.nih.gov/2008/sicklecell.htm [Accessed August 8, 2013]

Notes

1. Mechanism of action: Hydroxyurea is a ribonucleotide reductase inhibitor that blocks ribonucleoside conversion to deoxyribonucleotides and interferes with DNA synthesis. Hydroxyurea induces Hgb F expression by a mechanism of erythroid regeneration that induces F-cell production. In adults, F-cells are rare erythrocytes that contain small amounts of Hgb F. Enhanced concentrations of Hgb F in F-cells can inhibit Hgb S polymerization and RBC sickling, and improve the course of SCD

2. Duration of therapy: A long-term observational follow-up study of mortality in patients with SCD in the original MSH trial (Multicenter Study of Hydroxyurea) was conducted from 1996–2001. Two-hundred thirty-three (77.9%) of the original 299 patients were enrolled in the MSH Patients' Follow-up: 52% and 16% received hydroxyurea for ≥1 year and <1 year, respectively. When analyzed according to original assignment (treatment vs. placebo) and regardless of a patient's postrandomization treatment choice, mortality rates were similar between groups (23.7% vs. 26.5%). Twenty-five percent of patients (N = 75) died during the original trial or during follow-up. Of these, 28% died from pulmonary disease and 12% died during SCD crisis

Notes:

• Continue treatment indefinitely in patients who benefit from therapy and have no toxicity

• If Hgb F (or MCV) does not increase, consider poor compliance or biological inability to respond. A trial period of 6–12 months without transfusion support is adequate provided the patient does not suffer an intercurrent illness that suppresses erythropoiesis

Cumulative mortality in the MSH trial analyzed according to clinical events and laboratory measurements at the conclusion of randomized treatment showed the following:

Notes:

A systematic evidence review of the barriers to hydroxyurea found only 3 studies that specifically addressed this issue and none that tested interventions to overcome barriers to hydroxyurea treatment in SCD

System-level barriers included: (1) financing (lack of insurance, type of insurance, underinsurance, scope of coverage, copays, reimbursement, and payment structures); (2) lack of coordination between academic centers and community-based clinicians; (3) geographic isolation; (4) limited access to comprehensive care centers and care models; (5) problems in transitioning from pediatric to adult care; (6) limited access; (7) inadequate government, industry, and philanthropic support; (8) slow development and promotion of hydroxyurea because of lack of commercial interest; (9) lack of visibility/empowerment of SCD advocacy groups; (10) cultural and language barriers; and (11) inadequate information technology systems to support long-term care of SCD patients

Monitoring Therapy

Treatment monitoring end points include:

• Less pain

• Improved well-being

• Increase in Hgb F to 15–20%

• Increased Hgb level if severely anemic

• Acceptable myelotoxicity

Laboratory Monitoring:

Baseline:

1. CBC with differential, RBC indices, percent Hgb F, serum creatinine and BUN, liver function tests, renal panel, and pregnancy test in females

After initiation:

1. Every 2 weeks: CBC with differential

2. Every 2–4 weeks: Serum creatinine and BUN, LFTs, and renal panel

3. Every 6–8 weeks: Percent Hgb F

After a stable and nontoxic dose is reached:

1. Every 4–8 weeks: CBC with differential as long as ANC ≥2000/mm³ and platelets and reticulocytes are ≥80,000/mm³; periodic LFT monitoring is advised

Red Blood Cell Transfusion

Hemolytic Transfusion Reactions. In: Petz L, Garratty G, eds. Immune Hemolytic Anemias. 2nd ed. Philadelphia, PA: Churchill Livingstone; 2004:541–572

Ohene-Frempong K. Semin Hematol 2001;38(1 Suppl 1):5–13

The Management of Sickle Cell Disease, 4th ed. NIH Publication No. 02-2117. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; 2002. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf [accessed August 5, 2013]

Vichinsky EP et al. N Engl J Med 1995;333:206–213

Most appropriate RBC product:

1. Phenotypically matched, sickle-negative, leukocyte-depleted packed RBCs

2. Administer washed RBCs if a patient had an allergic reaction to prior transfusions

3. Irradiation of RBCs is recommended in patients who are likely candidates for BMT

Methods of transfusion

1. Simple transfusion

   • Acute transfusion

     Note: Volume overload can occur when a large volume of blood is transfused too quickly. The administration of intravenous diuretics, slowing the rate of transfusion or partial removal of red cell supernatant fluid can help to prevent this complication

   • Chronic transfusion: Simple transfusion every 2–4 weeks to maintain a Hgb A level at 60–70%. The pretransfusion Hct should be between 25% and 30% and posttransfusion Hct ≤36% to prevent hyperviscosity

2. Exchange transfusion: The final Hgb should not exceed the range of 10–12 g/dL to avoid hyperviscosity and the percentage of Hgb A should meet the goals of therapy (60–70% normal Hgb A)

3. RBC apheresis

Review transfusion goals before starting

1. Assess for appropriate indication

2. Set goals for final posttransfusion hematocrit or Hgb and % Hgb S (avoid Hct >36%)

   • Major Surgery: Hgb 10 g/dL, Hgb S ~60% or less

   • Sudden severe illness: maintain Hgb S <30%

Patient Population Studied

Indications

1. Acute pain episodes complicated by sufficient physiologic derangement to result in heart failure, dyspnea, hypotension, or marked fatigue

2. Acute chest syndrome, systemic fat embolization, and stroke

3. Acute splenic sequestration

4. Multiorgan failure syndrome

5. Transient red blood cell aplasia or "aplastic crisis"

6. Severe anemia in patients with serious and potentially life-threatening infection

7. Hyperhemolysis where a Hgb level following transfusion is lower than that prior to transfusion; generally proposed to result from an increased rate of destruction of a patient's own RBCs. This may occur as a component of delayed hemolytic transfusion reactions or occasionally from an underlying G6PD deficiency, and may occur as a consequence of occult splenic sequestration or aplastic crises detected during a period of resolving reticulocytosis (Petz LD et al. Transfusion 1997;37:382–392)

8. Before major surgery

9. Consider administering in pregnant patients with complications such as preeclampsia, severe anemia, increasing frequency of pain episodes, women with previous pregnancy losses or who have multiple gestations

Controversial indications

1. Priapism

2. Leg ulcers

3. Preparation for infusion of hypertonic contrast media (gadolinium and nonionic contrast media lower the risk of RBC sickling)

4. Management of "silent" cerebral infarct and/or neurocognitive damage

Inappropriate indications and contraindications

1. Chronic steady-state anemia

2. Uncomplicated acute pain episodes

3. Uncomplicated infection

4. Minor surgery that does not require prolonged anesthesia (eg, myringotomy)

5. Aseptic necrosis of the shoulder or hip (except when surgery is required)

6. Uncomplicated pregnancies

Toxicity

1. Alloimmunization. The highest incidence is reported to be associated with SCD and AIHA. In a summary of 12 reports of 2818 transfused patients with SCD, alloimmunization occurred in 8–35% (mean and median, 25%)

   • Sickle cell hemolytic transfusion reaction: Manifestations of an acute or delayed hemolytic transfusion reaction where serologic studies may not provide an explanation for the hemolytic transfusion reaction

   • Development of symptoms suggestive of a sickle cell pain crisis that develop or are intensified by the hemolytic reaction

   • Development of a more severe anemia after transfusion than was previously present, with exacerbation of subsequent transfusions

   • Difficulty in finding compatible RBC units because of alloantibodies ± autoantibodies

2. Delayed hemolytic transfusion reaction: Four series in SCD reported an incidence of 4–22%; an incidence 10-times higher than for random transfused patients. Occurs 5–20 days after transfusion. Results from RBC antibodies are not present at the time of compatibility testing

3. Transfusion iron overload

4. Transmission of infection B19 parvovirus occurs in 1:40,000 RBC

5. Precipitation of pain episodes, strokes, acute pulmonary insufficiency

6. Hyperviscosity

7. Volume overload, when a large volume of blood is transfused too quickly

Notes

In a randomly assigned cohort of 551 patients with sickle cell disease undergoing 604 operations, a conservative transfusion regimen (designed to increase preoperative Hgb to 10 g/dL, regardless of Hgb S) was found to be as effective as an aggressive transfusion regimen (designed to maintain a preoperative Hgb at 10 g/dL; Hgb S ≤30%) in preventing serious complications (35% vs. 31%) and the development of acute chest (each regimen 10%), but was associated with half as many transfusion-associated complications (Vichinsky EP et al. N Engl J Med 1995;333:206–213)