Managing Acute Complications of Sickle Cell Disease in Pediatric Patients (Pharmacology CME)

Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction And Epidemiology
4. Critical Appraisal of the Literature
5. Etiology And Pathophysiology
6. Differential Diagnosis
   1. Vaso-Occlusive Crisis
   2. Acute Chest Syndrome
   3. Febrile Illness
   4. Splenic Sequestration
   5. Stroke
7. Prehospital Care
8. Emergency Department Evaluation
   1. History And Physical Examination
      1. Vaso-Occlusive Crisis
      2. Acute Chest Syndrome
      3. Febrile Illness
      4. Splenic Sequestration
      5. Stroke
      6. Priapism
9. Diagnostic Studies
   1. Vaso-Occlusive Crisis
   2. Acute Chest Syndrome
   3. Febrile Illness
   4. Splenic Sequestration
   5. Stroke
   6. Priapism
10. Management
    1. Vaso-Occlusive Crisis
       1. Analgesia
       2. Hydration
       3. Nonpharmacologic Therapies
    2. Acute Chest Syndrome
       1. Supplemental Oxygen
       2. Blood Transfusions
       3. Corticosteroids
    3. Fever In Sickle Cell Disease
    4. Splenic Sequestration
    5. Stroke
    6. Priapism
       1. Aspiration Of Corpora Cavernosa
11. Special Populations And Circumstances
    1. Patients With Sickle Cell Trait
       1. Exertional Collapse Associated With Sickle Cell Trait
       2. Hematuria
       3. Traumatic Hyphema
    2. Pregnancy And Sickle Cell Disease
    3. Unvaccinated Children
    4. Infections With Human Parvovirus B19
    5. High Emergency Department Utilizers With Sickle Cell Disease Pain
12. Controversies And Cutting Edge
    1. Magnesium Sulfate Use In Vaso-Occlusive Crisis
    2. Corticosteroid Use In Vaso-Occlusive Crisis
    3. Nitric Oxide Use In Vaso-Occlusive Crisis
    4. Ketamine Use In Vaso-Occlusive Crisis
13. Disposition
14. Summary
15. Risk Management Pitfalls In Pediatric Patients With Sickle Cell Disease
16. Time- And Cost-Effective Strategies
17. Case Conclusions
18. Clinical Pathway For Pain Management In Vaso-Occlusive Crisis In Children With Sickle Cell Disease
19. Tables And Figures
    1. Table 1. Common Genotypes Of Sickle Cell Hemoglobinopathies And Their Characteristics
    2. Table 2. Differential Diagnosis Of Acute Complications In Sickle Cell Disease
    3. Table 3. Management Of Acute Complications Of Sickle Cell Disease
    4. Figure 1. Oxygen Dissociation Curve Of Hemoglobin A Versus Hemoglobin S
    5. Figure 2. X-Ray Of Right-Sided Infiltrate In A Child With Acute Chest Syndrome
    6. Figure 3. Magnetic Resonance Imaging Scan Of Axial Fluid Attenuation Inversion Recovery
20. References

Abstract

Sickle cell disease is a chronic hematologic disease with a variety of acute, and often recurring, complications. Vaso-occlusive crisis, a unique but common presentation in sickle cell disease, can be challenging to manage. Acute chest syndrome is the leading cause of death in patients with sickle cell disease, occurring in more than half of patients who are hospitalized with a vaso-occlusive crisis. Uncommon diagnoses in children, such as stroke, priapism, and transient red cell aplasia, occur more frequently in patients with sickle cell disease and necessitate a degree of familiarity with the disease process and its management. Patients with sickle cell trait generally have a benign course, but are also subject to serious complications. This issue provides a current review of evidence-based management of the most common acute complications of sickle cell disease seen in pediatric patients in the emergency department.

Case Presentations

An 18-year-old adolescent girl with sickle cell disease presents to the ED stating she has severe bilateral thigh and shoulder pain. On examination, she has normal vital signs and appears comfortable lying on her gurney. She reports mild pain when her shoulder and thighs are palpated. A nurse comments that she had also presented 2 days ago, and is possibly seeking drugs. How do you decide whether this is drug-seeking behavior or pain from vaso-occlusive crisis? What pain medication can you offer her? How do you decide whether she will need to be admitted for pain control?

A 12-year-old boy with sickle cell disease is brought in by EMS because he is having trouble breathing. He is coughing and complains of right-sided chest pain. On examination, he appears to be in severe respiratory distress. His vital signs are: respiratory rate, 50 breaths/ min; oxygen saturation, 89% on room air; temperature, 37°C (98.6°F); heart rate, 110 beats/min; and blood pressure, 110/70 mm Hg. On auscultation of the lungs, you hear crackles bilaterally. A chest x-ray shows a right-sided infiltrate. The resident is placing him on a nonrebreather mask. What is the diagnosis of this patient? What treatment should be started? Is there any role for a blood transfusion?

A 4-year-old boy with sickle cell disease is brought in by his father because the child developed a fever today. Prior to fever onset, the child was in school, and was his usual, active self. On examination, he has a fever of 38.9°C (102°F), but all other vital signs are normal. He appears well and is playful for the rest of the examination. Should you obtain any laboratory studies? Does he need antibiotics?

An 18-month-old toddler with sickle cell disease is brought in by his mother because he looks pale and tired. His vital signs are: respiratory rate, 30 breaths/min; oxygen saturation, 97% on room air; temperature, 37°C (98.6°F); heart rate, 142 beats/ min; and blood pressure, 88/60 mm Hg. He appears alert and comfortable. You note a large spleen on examination. What steps should you take next? Does this patient need to be admitted or can he be discharged home if all tests are normal?

Introduction And Epidemiology

Sickle cell disease (SCD) refers to a family of genetic blood disorders caused by the sickling of red blood cells secondary to atypical hemoglobin molecules, known as hemoglobin S (HbS). This disease is seen primarily in individuals of African, Indian, Mediterranean, or Saudi Arabian ancestry.¹ Annually, 200,000 children are born with SCD worldwide. Ninety percent of these births are in sub-Saharan Africa. In the United States, 1 in 2474 births are children with SCD. The national prevalence is between 70,000 to 140,000 patients, mostly in those of African ancestry.²

SCD has wide-ranging implications to human physiology. Newborns inherit the autosomal recessive genes from their biological parents. The pathophysiological processes that alter the properties of the red blood cell begin in infancy, with effects seen through adulthood. The following common acute complications (listed in order or prevalence) will be discussed:

• Vaso-occlusive crisis (VOC)³
• Acute chest syndrome (ACS)^3,4
• Priapism⁵
• Splenic sequestration^6,7
• Stroke⁸
• Bacteremia⁹

Emergency clinicians are first-line providers in the care of patients with acute SCD complications. As such, an understanding of the pathophysiology, clinical features, and management is essential to providing high-quality care. This issue of Pediatric Emergency Medicine Practice provides an overview of SCD and recommendations for the management of some of the most common complications seen in pediatric patients with SCD.

Critical Appraisal Of The Literature

A literature search was performed in PubMed using the terms sickle cell, pain, vaso-occlusion, hemolysis, fever, sepsis, wheeze, acute chest syndrome, stroke, splenic sequestration, transient red cell aplasia, and priapism. Over 500 articles from 1961 to 2015 were reviewed. The Cochrane Database of Systematic Reviews was searched using the key words sickle cell; 52 studies were reviewed. The American College of Emergency Physicians (ACEP) and American Society of Hematology (ASH) websites were reviewed; neither have issued SCD policy statements or guidelines. The American Academy of Pediatrics (AAP) Section on Hematology/Oncology and Committee on Genetics issued a policy statement on health supervision for children with SCD that was reaffirmed in 2006 and 2011.¹⁰ The June 2014 publication by the National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) expert panel report on SCD was reviewed.¹¹ The AAP endorsed this report in November 2014. The comprehensive report included consensus statements and evidence-based guidelines. Using a modified Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) standard evidence scale, there was only 1 high-quality, strongly recommended finding for management of acute SCD complications.¹² All other recommendations used moderate- to low-quality evidence. Between 1995 and 2010, only 12 randomized controlled trials were conducted for acute complications of SCD in children.¹³ Reasons for this lack of high-quality evidence for management of acute complications are likely due to the rarity of the genetic disorder, poor funding for research, and the discovery of successful breakthrough health main-tenance interventions (ie, immunizations, penicillin prophylaxis, regular blood transfusions, and hydroxyurea use).^14,15

Risk Management Pitfalls In Pediatric Patients With Sickle Cell Disease

1. “The patient says she is in pain, but her heart rate, respiratory rate, and blood pressure are normal. Is she malingering?”
   Patients with SCD who state that they are in pain need to be treated compassionately and with urgency to alleviate their pain. The majority of patients with VOC have normal vital signs even when severe pain is reported.
    
2. “This SCD patient complaining of right knee pain must be having a VOC episode even though it is not his usual site for VOC pain.”
   Although patients with SCD experience VOC more commonly than other complications, there is a broad differential to consider. Extremity pain can be due to many reasons, including fracture, osteomyelitis, septic arthritis, or sports injuries.
    
3. “I want to give a fluid bolus to this patient who is experiencing his usual VOC.”
   Fluid boluses are not recommended for VOC treatment unless the patient is volume-deficient. Oral fluids should be encouraged. If the patient is not able to tolerate oral intake, then intravenous fluids should be started at the maintenance rate.
    
4. “He looks so well, this cough and fever must be from a viral upper respiratory tract infection.”
   Patients with SCD presenting with cough and fever need to be evaluated for ACS and should receive imaging of the chest. A new infiltrate on CXR in combination with features such as cough or fever meet the definition of ACS.
    
5. “The headache of this SCD patient with no prior transfusions is probably a common tension headache.”
   Remember that children with SCD are at risk for stroke. Those who meet the criteria for being at high risk for stroke may be on regular transfusions to prevent this. Headaches are a feature of stroke and require detailed evaluation.
    
6. “We should transfuse this patient with priapism since it has lasted more than 4 hours.”
   There is no role for transfusion in priapism. Past the 4-hour time point, priapism causes irreversible erectile tissue damage. After consulting urology, emergency clinicians should begin aspiration and irrigation to salvage erectile tissue.
    
7. “There is no place for starting this patient on incentive spirometry because he is admitted for VOC, not ACS”
   Incentive spirometry should be started on patients with SCD being admitted for VOC management, as it prevents the development of ACS during the patient’s inpatient stay.
    
8. “This 19-year-old HbSC patient has left-sided abdominal pain. It cannot be splenic sequestration.”
   In HbSC, splenic tissue is present in sufficient quantity that splenic sequestration is a possibility. Adolescents and adults can experience sickle cell sequestration and it should be included in the differential when managing these SCD genotypes.
    
9. “Since this patient has sickle cell trait, he has no problems to worry about.”
   Individuals who carry 1 gene that codes for HbS are at risk for several medical problems, including renal medullary carcinoma, renal papillary necrosis, splenic infarcts, and exercise-related deaths.
    
10. “He’s of Indian origin, so he does not have SCD.”
    The sickle cell genotype originated from areas endemic for Plasmodium falciparum malaria. This means people of Indian, African, Middle Eastern, and Mediterranean descent could be carriers or be homozygous for the gene.

Tables And Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. The most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

1. Quinn CT. Sickle cell disease in childhood: from newborn screening through transition to adult medical care. Pediatr Clin North Am. 2013;60(6):1363-1381. (Review)
2. Kanter J, Kruse-Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev. 2013;27(6):279-287. (Review)
3. Neonato MG, Guilloud-Bataille M, Beauvais P, et al. Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur J Haematol. 2000;65(3):155-164. (Prospective and retrospective study; 299 patients)
4. * Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. 1994;84(2):643-649. (Prospective study; 3751 patients)
5. Adeyoju AB, Olujohungbe AB, Morris J, et al. Priapism in sickle-cell disease; incidence, risk factors and complications - an international multicentre study. BJU Int. 2002;90(9):898- 902. (Descriptive survey study; 130 patients)
6. Brousse V, Elie C, Benkerrou M, et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol. 2012;156(5):643-648. (Retrospective cohort study; 190 patients)
7. McCavit TL. Sickle cell disease. Pediatr Rev. 2012;33(5):195- 204. (Review)
8. Musallam KM, Khoury RA, Abboud MR. Cerebral infarction in children with sickle cell disease: a concise overview. Hemoglobin. 2011;35(5-6):618-624. (Review)
9. Hirst C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev. 2014;11:CD003427. (Systematic review)
10. Health supervision for children with sickle cell disease. Pediatrics. 2002;109(3):526-535. (Consensus statement)
11. * Evidence-based management of sickle cell disease: expert panel report 2014. National Institutes of Health: National Heart, Lung and Blood Institute; 2014:31-53. (Expert panel report)
12. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048. (Expert panel report)
13. Kavanagh PL, Sprinz PG, Vinci SR, et al. Management of children with sickle cell disease: a comprehensive review of the literature. Pediatrics. 2011;128(6):e1552-e1574. (Literature review)
14. Glassberg J. Evidence-based management of sickle cell disease in the emergency department. Emerg Med Pract. 2011;13(8):1-20. (Review)
15. Prabhakar H, Haywood C Jr, Molokie R. Sickle cell disease in the United States: looking back and forward at 100 years of progress in management and survival. Am J Hematol. 2010;85(5):346-353. (Review)
16. Benson JM, Therrell BL Jr. History and current status of newborn screening for hemoglobinopathies. Semin Perinatol. 2010;34(2):134-144. (Review)
17. Glassberg JA, Strunk R, DeBaun MR. Wheezing in children with sickle cell disease. Curr Opin Pediatr. 2014;26(1):9-18. (Review)
18. Chakravorty S, Williams TN. Sickle cell disease: a neglected chronic disease of increasing global health importance. Arch Dis Child. 2015;100(1):48-53. (Review)
19. Meier ER, Miller JL. Sickle cell disease in children. Drugs. 2012;72(7):895-906. (Review)
20. Redding-Lallinger R, Knoll C. Sickle cell disease--pathophysiology and treatment. Curr Probl Pediatr Adolesc Health Care. 2006;36(10):346-376. (Review)
21. Kassim AA, Galadanci NA, Pruthi S, et al. How I treat and manage strokes in sickle cell disease. Blood. 2015;125(22):3401-3410. (Review)
22. Ejindu VC, Hine AL, Mashayekhi M, et al. Musculoskeletal manifestations of sickle cell disease. Radiographics. 2007;27(4):1005-1021. (Review)
23. Naik RP, Steriff MB, Haywood C Jr, et al. Venous thromboembolism incidence in the Cooperative Study of Sickle Cell Disease. J Thromb Haemost. 2014;12(12): 2010-2016. (Observational cohort)
24. Battersby AJ, Knox-Macaulay HH, Carrol ED. Susceptibility to invasive bacterial infections in children with sickle cell disease. Pediatr Blood Cancer. 2010;55(3):401-406. (Review)
25. Shilo NR, Lands LC. Asthma and chronic sickle cell lung disease: a dynamic relationship. Paediatr Respir Rev. 2011;12(1):78-82. (Review)
26. Gilboy N, Tanabe P, Travers D, et al. Emergency Severity Index (ESI): A Triage Tool for Emergency Department Care, Version 4. Implementation Handbook 2012 Edition. Agency for Healthcare Research and Quality; 2011. (Handbook)
27. Frei-Jones MJ, Baxter AL, Rogers ZR, et al. Vaso-occlusive episodes in older children with sickle cell disease: emergency department management and pain assessment. J Pediatr. 2008;152(2):281-285. (Retrospective study; 105 patients, 279 VOC episodes)
28. Mousa SA, Al Momen A, Al Sayegh F, et al. Management of painful vaso-occlusive crisis of sickle-cell anemia: consensus opinion. Clin Appl Thromb Hemost. 2010;16(4):365-376. (Review)
29. Almeida A, Roberts I. Bone involvement in sickle cell disease. Br J Haematol. 2005;129(4):482-490. (Review)
30. Serjeant GR, Ceulaer CD, Lethbridge R, et al. The painful crisis of homozygous sickle cell disease: clinical features. Br J Haematol. 1994;87(3):586-591. (Prospective study; 118 patients, 183 VOC episodes)
31. Mathias MD, McCavit TL. Timing of opioid administration as a quality indicator for pain crises in sickle cell disease. Pediatrics. 2015;135(3):475-482. (Single-center retrospective study; 177 patients, 414 VOC episodes)
32. Bartolucci P, El Murr T, Roudot-Thoraval F, et al. A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults. Blood. 2009;114(18):3742- 3747. (Randomized controlled trial; 66 VOC episodes)
33. Ernst AA, Weiss SJ, Johnson WD, et al. Blood pressure in acute vaso-occlusive crises of sickle cell disease. South Med J. 2000;93(6):590-592. (Retrospective study; 231 patients)
34. Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011;305(9):893-902. (Prospective, multicenter, double-blinded, randomized, placebo-controlled trial; 150 patients)
35. * Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease. Blood. 1997;89(5):1787-1792. (Multicenter prospective cohort study; 939 patients, 1722 ACS episodes)
36. Abbas HA, Kahale M, Hosn MA, et al. A review of acute chest syndrome in pediatric sickle cell disease. Pediatr Ann. 2013;42(3):115-120. (Review)
37. Lovett PB, Sule HP, Lopez BL. Sickle cell disease in the emergency department. Emerg Med Clin North Am. 2014;32(3):629- 647. (Review)
38. Comber JT, Lopez BL. Evaluation of pulse oximetry in sickle cell anemia patients presenting to the emergency department in acute vasoocclusive crisis. Am J Emerg Med. 1996;14(1):16- 18. (Prospective study; 13 patients)
39. Blaisdell CJ, Goodman S, Clark K, et al. Pulse oximetry is a poor predictor of hypoxemia in stable children with sickle cell disease. Arch Pediatr Adolesc Med. 2000;154(9):900-903. (Prospective study; 21 patients)
40. * Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med. 1986;314(25):1593-1599. (Multicenter randomized controlled trial; 215 patients)
41. Serjeant GR. Treatment of sickle cell disease in early childhood in Jamaica. Am J Pediatr Hematol Oncol. 1985;7(3): 235-239. (Review)
42. Konotey-Ahulu FID, Serjeant G, White JM et al. Treatment and prevention of sickle cell crisis. The Lancet. 1971;298(7736): 1255-1256. (Commentary)
43. * Leikin SL, Gallagher D, Kinney TR, et al. Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics. 1989;84(3):500-508. (Multicenter prospective cohort study; 2824 patients)
44. Airede AI. Acute splenic sequestration in a five-week-old infant with sickle cell disease. J Pediatr. 1992;120(1):160. (Case report)
45. Owusu-Ofori S, Hirst C. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev. 2013;5:CD003425. (Systematic review)
46. Koduri PR, Nathan S. Acute splenic sequestration crisis in adults with hemoglobin S-C disease: a report of nine cases. Ann Hematol. 2006;85(4):239-243. (Case report; 9 patients)
47. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288-294. (Multicenter prospective cohort study; 4082 patients)
48. Strouse JJ, Hulbert ML, DeBaun MR, et al. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics. 2006;118(5):1916-1924. (Retrospective case-control study; 44 patients)
49. Roach ES, Golomb MR, Adams R, et al. Management of stroke in infants and children: a scientific statement from a special writing group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008;39(9):2644-2691. (Consensus statement)
50. Mantadakis E, Cavender JD, Rogers ZR, et al. Prevalence of priapism in children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol. 1999;21(6):518-522. (Descriptive survey study; 98 patients)
51. Donaldson JF, Rees RW, Steinbrecher HA. Priapism in children: a comprehensive review and clinical guideline. J Pediatr Urol. 2014;10(1):11-24. (Review)
52. Anele UA, Le BV, Resar LM, et al. How I treat priapism. Blood. 2015;125(23):3551-3558. (Review)
53. Bernard AW, Venkat A, Lyons MS. Best evidence topic report. Full blood count and reticulocyte count in painful sickle crisis. Emerg Med J. 2006;23(4):302-303. (Review)
54. Mohammed FA, Mahdi N, Sater MA, et al. The relation of C-reactive protein to vasoocclusive crisis in children with sickle cell disease. Blood Cells Mol Dis. 2010;45(4):293-296. (Prospective study; 144 patients)
55. Najim OA, Hassan MK. Lactate dehydrogenase and severity of pain in children with sickle cell disease. Acta Haematol. 2011;126(3):157-162. (Prospective descriptive study; 76 patients)
56. Stuart J, Stone PC, Akinola NO, et al. Monitoring the acute phase response to vaso-occlusive crisis in sickle cell disease. J Clin Pathol. 1994;47(2):166-169. (Prospective longtitudinal study; 10 patients, 14 VOC episodes)
57. Keikhaei B, Mohseni AR, Norouzirad R, et al. Altered levels of pro-inflammatory cytokines in sickle cell disease patients during vaso-occlusive crises and the steady state condition. Eur Cytokine Netw. 2013;24(1):45-52. (Prospective study; 54 patients)
58. Sarray S, Saleh LR, Lisa Saldanha F, et al. Serum IL-6, IL-10, and TNFalpha levels in pediatric sickle cell disease patients during vasoocclusive crisis and steady state condition. Cytokine. 2015;72(1):43-47. (Prospective study; 210 patients)
59. Pereda MA, Chavez MA, Hooper-Miele CC, et al. Lung ultrasound for the diagnosis of pneumonia in children: a meta-analysis. Pediatrics. 2015;135(4):714-722. (Meta-analysis)
60. Daswani DD, Shah VP, Avner JR, et al. Accuracy of point-of-care lung ultrasonography for diagnosis of acute chest syndrome in pediatric patients with sickle cell disease and fever. Acad Emerg Med. 2016;23(8):932-940. (Prospective study; 91 patients, 116 events)
61. Reed L, Carroll J, Cumming A, et al. Serum lactate as a screening tool and predictor of outcome in pediatric patients presenting to the emergency department with suspected infections. Pediatr Emerg Care. 2013;29(7):787-91 (Retrospective study)
62. Scott HF, Donoghue AJ, Galeski DF, et al. The utility of early lactate testing in undifferentiated pediatric systemic inflammatory response syndrome. Acad Emerg Med. 2012;19(11):1276-80 (Prospective cohort study; 239 patients)
63. Fiebach JB, Schellinger PD, Gass A, et al. Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging. Stroke. 2004;35(2):502-506. (Multicenter prospective study; 124 patients)
64. Lansberg MG, Albers GW, Beaulieu C, et al. Comparison of diffusion-weighted MRI and CT in acute stroke. Neurology. 2000;54(8):1557-1561. (Prospective study; 19 patients)
65. Olujohungbe A, Burnett AL. How I manage priapism due to sickle cell disease. Br J Haematol. 2013;160(6):754-765. (Review)
66. Leong MA, Dampier C, Varlotta L, et al. Airway hyperreactivity in children with sickle cell disease. J Pediatr. 1997;131(2):278-283. (Prospective study; 40 patients)
67. * Baskin MN, Goh XL, Heeney MM, et al. Bacteremia risk and outpatient management of febrile patients with sickle cell disease. Pediatrics. 2013;131(6):1035-1041. (Retrospective cohort study; 1118 febrile episodes)
68. Beiter JL Jr, Simon HK, Chambliss CR, et al. Intravenous ketorolac in the emergency department management of sickle cell pain and predictors of its effectiveness. Arch Pediatr Adolesc Med. 2001;155(4):496-500. (Prospective case series; 51 patients)
69. Dunlop RJ, Bennett KC. Pain management for sickle cell disease. Cochrane Database Syst Rev. 2006(2):CD003350. (Systematic review)
70. * Jacobson SJ, Kopecky EA, Joshi P, et al. Randomised trial of oral morphine for painful episodes of sickle-cell disease in children. Lancet. 1997;350(9088):1358-1361. (Double-blinded randomized controlled trial; 56 patients)
71. Field JJ, Knight-Perry JE, Debaun MR. Acute pain in children and adults with sickle cell disease: management in the absence of evidence-based guidelines. Curr Opin Hematol. 2009;16(3):173-178. (Review)
72. Melzer-Lange MD, Walsh-Kelly CM, Lea G, et al. Patient-controlled analgesia for sickle cell pain crisis in a pediatric emergency department. Pediatr Emerg Care. 2004;20(1):2-4. (Prospective study; 69 patients)
73. Okomo U, Meremikwu MM. Fluid replacement therapy for acute episodes of pain in people with sickle cell disease. Cochrane Database Syst Rev. 2007(2):CD005406. (Systematic review)
74. Guy RB, Gavrillis PK, Rothenberg SP. In vitro and in vivo effect of hypotonic saline on the sickling phenomenon. Am J Med Sci. 1973;266(4):267-277 (Prospective study; 7 patients)
75. Uman LS, Birnie KA, Noel M, et al. Psychological interventions for needle-related procedural pain and distress in children and adolescents. Cochrane Database Syst Rev. 2013;10:CD005179. (Systematic review)
76. Beyer JE, Simmons LE. Home treatment of pain for children and adolescents with sickle cell disease. Pain Manag Nurs. 2004;5(3):126-135. (Prospective study; 42 patients)
77. Bender MA, Douthitt Seibel G. Sickle cell disease. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R): University of Washington, Seattle. All rights reserved; 1993. (Review)
78. Ahmad FA, Macias CG, Allen JY. The use of incentive spirometry in pediatric patients with sickle cell disease to reduce the incidence of acute chest syndrome. J Pediatr Hematol Oncol. 2011;33(6):415-420. (Retrospective cohort study; 1551 patient visits)
79. Wilson BH, Nelson J. Sickle cell disease pain management in adolescents: a literature review. Pain Manag Nurs. 2015;16(2):146-151. (Review)
80. * Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342(25):1855-1865. (Multicenter prospective cohort study; 538 patients, 671 ACS episodes)
81. Neumayr L, Lennette E, Kelly D, et al. Mycoplasma disease and acute chest syndrome in sickle cell disease. Pediatrics. 2003;112(1 Pt 1):87-95. (Multicenter prospective cohort study; 538 patients, 671 ACS episodes)
82. Marti-Carvajal AJ, Conterno LO. Antibiotics for treating community acquired pneumonia in people with sickle cell disease. Cochrane Database Syst Rev. 2012;10:CD005598. (Systematic review)
83. Marti-Carvajal AJ, Conterno LO, Knight-Madden JM. Antibiotics for treating acute chest syndrome in people with sickle cell disease. Cochrane Database Syst Rev. 2015;3:CD006110. (Systematic review)
84. Knight-Madden JM, Hambleton IR. Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease. Cochrane Database Syst Rev. 2014;8:CD003733. (Systematic review)
85. Turner JM, Kaplan JB, Cohen HW, et al. Exchange versus simple transfusion for acute chest syndrome in sickle cell anemia adults. Transfusion. 2009;49(5):863-868. (Retrospective study)
86. Alhashimi D, Fedorowicz Z, Alhashimi F, et al. Blood transfusions for treating acute chest syndrome in people with sickle cell disease. Cochrane Database Syst Rev. 2010(1):CD007843. (Systematic review)
87. Bernini JC, Rogers ZR, Sandler ES, et al. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood. 1998;92(9):3082-3089. (Randomized, double-blinded, placebo-controlled trial; 38 children, 43 episodes)
88. Sobota A, Graham DA, Heeney MM, et al. Corticosteroids for acute chest syndrome in children with sickle cell disease: variation in use and association with length of stay and readmission. Am J Hematol. 2010;85(1):24-28. (Retrospective study; 5247 hospitalizations)
89. Ogunlesi F, Heeney MM, Koumbourlis AC. Systemic corticosteroids in acute chest syndrome: friend or foe? Paediatr Respir Rev. 2014;15(1):24-27. (Review)
90. Strikas RA. Advisory committee on immunization practices recommended immunization schedules for persons aged 0 through 18 years--United States, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(4):93-94. (Clinical practice guidelines)
91. Farnham AC, Zimmerman CM, Papadouka V, et al. Invasive Pneumococcal Disease Following the Introduction of 13-Valent Conjugate Vaccine in Children in New York City From 2007 to 2012. JAMA Pediatr. 2015. (Retrospective population-based analysis; 468 cases)
92. The management of sickle cell disease. National Institute of Health: National Heart, Lung and Blood Institute; 2002. (Expert panel report)
93. Rhodes MM, Bates DG, Andrews T, et al. Abdominal pain in children with sickle cell disease. J Clin Gastroenterol. 2014;48(2):99-105. (Review)
94. Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. J Pediatr. 2006;149(5):710-712. (Retrospective cohort study; 137 patients)
95. DeBaun MR. Secondary prevention of overt strokes in sickle cell disease: therapeutic strategies and efficacy. Hematology Am Soc Hematol Educ Program. 2011;2011:427-433. (Review)
96. Broderick GA, Kadioglu A, Bivalacqua TJ, et al. Priapism: pathogenesis, epidemiology, and management. J Sex Med. 2010;7(1 Pt 2):476-500. (Review)
97. Dallimore D, Herd DW, Short T, et al. Dosing ketamine for pediatric procedural sedation in the emergency department. Pediatr Emerg Care. 2008;24(8):529-33. (Statistical simulation study)
98. Jesus LE, Dekermacher S. Priapism in children: review of pathophysiology and treatment. J Pediatr (Rio J). 2009;85(3):194-200. (Review)
99. Mantadakis E, Ewalt DH, Cavender JD, et al. Outpatient penile aspiration and epinephrine irrigation for young patients with sickle cell anemia and prolonged priapism. Blood. 2000;95(1):78-82. (Prospective study; 15 patients, 39 priapic episodes)
100. King C, Henretig FM, eds. Textbook of Pediatric Emergency Procedures, Second Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2008. (Textbook)
101. * Montague DK, Jarow J, Broderick GA, et al. American Urological Association guideline on the management of priapism. J Urol. 2003;170(4 Pt 1):1318-1324. (Clinical practice guideline)
102. Kark JA PD, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. 1987;24;317(13):781-787. (Retrospective study)
103. O’Connor FG, Bergeron MF, Cantrell J, et al. ACSM and CHAMP summit on sickle cell trait: mitigating risks for warfighters and athletes. Med Sci Sports Exerc. 2012;44(11):2045- 2056. (Expert panel report)
104. Alappan N, Marak CP, Chopra A, et al. Renal medullary cancer in a patient with sickle cell trait. Case Rep Oncol Med. 2013;2013:129813. (Case report)
105. Chan TY. Book reviews: World Health Organization classification of tumours: pathology & genetics of tumours of the urinary system and male genital organs. Urology. 2005;65:214-215. (Textbook)
106. Tsaras G, Owusu-Ansah A, Boateng FO, et al. Complications associated with sickle cell trait: a brief narrative review. Am J Med. 2009;122(6):507-512. (Review)
107. Key NS, Derebail VK. Sickle-cell trait: novel clinical significance. Hematology. 2010;2010:418-422. (Review)
108. Nasrullah A, Kerr NC. Sickle cell trait as a risk factor for secondary hemorrhage in children with traumatic hyphema. Am J Ophthalmol. 1997;123(6):783-790. (Retrospecive chart review; 99 eyes)
109. Oteng-Ntim E, Meeks D, Seed PT, et al. Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. Blood. 2015;125(21):3316- 3325. (Systematic review and meta-analysis)
110. Okusanya BO, Oladapo OT. Prophylactic versus selective blood transfusion for sickle cell disease in pregnancy. Cochrane Database Syst Rev. 2013;12:CD010378. (Systematic review)
111. Hord J, Byrd R, Stowe L, et al. Streptococcus pneumoniae sepsis and meningitis during the penicillin prophylaxis era in children with sickle cell disease. J Pediatr Hematol Oncol. 2002;24(6):470-472. (Multicenter retrospective chart review; 5885 patient-years)
112. Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2007;44(11):1428- 1433. (Retrospective data analysis; 2026 cases)
113. Davies EG, Riddington C, Lottenberg R, et al. Pneumococcal vaccines for sickle cell disease. Cochrane Database Syst Rev. 2004(1):CD003885. (Systematic review)
114. Sox CM, Cooper WO, Koepsell TD, et al. Provision of pneumococcal prophylaxis for publicly insured children with sickle cell disease. JAMA. 2003;290(8):1057-1061. (Retrospecive longtitudinal study; 5 years)
115. Smith-Whitley K, Zhao H, Hodinka RL, et al. Epidemiology of human parvovirus B19 in children with sickle cell disease. Blood. 2004;103(2):422-427. (Prospective comparative study; 633 patients)
116. Crabol Y, Terrier B, Rozenberg F, et al. Intravenous im-munoglobulin therapy for pure red cell aplasia related to human parvovirus b19 infection: a rertrospective study of 10 patients and review of the literature. Clin Infect Dis. 2013;56(7):968-77. (Retrospective review, 36 patients)
117. Young NS. Parvovirus infection and its treatment. Clin Exp Immunol. 1996;1:26-30. (Review)
118. Donà D, Visentin F, Borgia E, et al. Acute human parvovirus B19 infection in a 6-year old girl with sickle cell disease: a case report. Open J Hematol. 2014;5(7):4. (Case report)
119. Boatright, DH, Abbott J. Not your typical frequent flyer: overcoming mythology in caring for sickle cell disease patients. Am J Bioeth. 2013;13(4):18-20. (Review)
120. Smith WR, Jordan LB, Hassell KL. Frequently asked questions by hospitalists managing pain in adults with sickle cell disease. J Hosp Med. 2011;6(5):297-303. (Review)
121. Badaki-Makun O, Scott JP, Panepinto JA, et al. Intravenous magnesium for pediatric sickle cell vaso-occlusive crisis: methodological issues of a randomized controlled trial. Pediatr Blood Cancer. 2014;61(6):1049-1054. (Descriptive report)
122. Brousseau DC, Scott JP, Hillery CA, et al. The effect of magnesium on length of stay for pediatric sickle cell pain crisis. Acad Emerg Med. 2004;11(9):968-972. (Prospective single-arm study; 19 patients)
123. Goldman RD, Mounstephen W, Kirby-Allen M, et al. Intravenous magnesium sulfate for vaso-occlusive episodes in sickle cell disease. Pediatrics. 2013;132(6):e1634-e1641. (Randomized, double-blinded, placebo-controlled trial; 106 patients)
124. Brousseau DC, Scott JP, Badaki-Makun O, et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood. 2015;126(14):1651- 1657. (Multicenter, randomized, double-blinded, placebo-controlled trial; 204 patients)
125. Griffin TC, McIntire D, Buchanan GR. High-dose intravenous methylprednisolone therapy for pain in children and adolescents with sickle cell disease. N Engl J Med. 1994;330(11):733-737. (Prospective, randomized, double-blinded study; 36 patients)
126. Rogers ZR, Dale JC, Bernini JC, et al. Dexamethasone shortens the duration of painful events requiring hospitalization in children with sickle cell disease: results of a randomized, double-blind, placebo-controlled trial. Blood. 1995;86(10):250a. (Randomized, double-blinded, placebo-controlled trial)
127. Moreira FT, de Oliveira CB, Gomez CM, et al. Is inhaled nitric oxide therapy more effective or safer than the conventional treatment for the treatment of vaso-occlusive crises in sickle-cell anemia? Rev Assoc Med Bras. 2011;57(3):253-254. (Systematic review)
128. Weiner DL, Hibberd PL, Betit P, et al. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA. 2003;289(9):1136-1142. (Prospective, double-blinded, placebo-controlled, randomized trial; 20 patients)
129. Head CA, Swerdlow P, McDade WA, et al. Beneficial effects of nitric oxide breathing in adult patients with sickle cell crisis. Am J Hematol. 2010;85(10):800-802. (Prospective, double-blinded, randomized, placebo-controlled trial; 23 patients)
130. Galeotti C, Courtois E, Carbajal R. How French paediatric emergency departments manage painful vaso-occlusive episodes in sickle cell disease patients. Acta Paediatr. 2014;103(12):e548-e554. (Descriptive survey study; 81 EDs)
131. Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014;93(5):769-771. (Review)
132. Zempsky WT, Loiselle KA, Corsi JM, et al. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010;26(2):163- 167. (Case series; 5 patients)
133. Meals CG, Mullican BD, Shaffer CM, et al. Ketamine infusion for sickle cell crisis pain in an adult. J Pain Symptom Manage. 2011;42(3):e7-e9. (Case report)
134. Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014;47(2):334-340. (Retrospective analysis; 9 patients)
135. Jennings CA, Bobb BT, Noreika DM, et al. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother. 2013;27(2):150-154. (Case report)
136. Chapman JI, El-Shammaa EN, Bonsu BK. The utility of screening laboratory studies in pediatric patients with sickle cell pain episodes. Am J Emerg Med. 2004;22(4):258-263. (Retrospective review; 86 visits)
137. Wells BL, Vizioli TL, Counselman FL. The reticulocyte count: is it needed for evaluating typical sickle cell crisis presenting to the ED? Am J Emerg Med. 2002;20(1):69-70. (Prospective blinded study; 34 patients, 101 visits)
138. Lopez BL, Griswold SK, Navek A, et al. The complete blood count and reticulocyte count--are they necessary in the evaluation of acute vasoocclusive sickle-cell crisis? Acad Emerg Med. 1996;3(8):751-757. (Retrospective chart review and prospective study; 323 patients)
139. * Bellet PS, Kalinyak KA, Shukla R, et al. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. N Engl J Med. 1995;333(11):699-703. (Prospective randomized trial; 29 patients)
140. Patel A. NICE guidance ignored incentive spirometry. Bmj. 2012;345:e5370. (Commentary)
141. Embury SH, Garcia JF, Mohandas N, et al. Effects of oxygen inhalation on endogenous erythropoietin kinetics, erythropoiesis, and properties of blood cells in sickle-cell anemia. N Engl J Med. 1984;311(5):291-295. (Observational study; 3 patients)
142. Lane PK, Embury SH, Toy PT. Oxygen-induced marrow red cell hypoplasia leading to transfusion in sickle painful crisis. Am J Hematol. 1988;27(1):67-68. (Case report)
143. Zipursky A, Robieux IC, Brown EJ, et al. Oxygen therapy in sickle cell disease. Am J Pediatr Hematol Oncol. 1992;14(3):222- 228. (Randomized controlled trial; 25 patients)