Chairman’s Rounds
August 13, 2010
David H. Rubin, MD
Department of Pediatrics, St. Barnabas
Hospital
Professor of Clinical Pediatrics,
Albert Einstein College of Medicine

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Case presentation
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History of sickle cell disease
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Pathophysiology
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Complications
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Treatment
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Competency Based Summary

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12 month old SC patient with fever for
2 days; tmax 103  F
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+ rhinorrhea, no cough
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Reduced oral intake and activity
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PE: T105.2
 F, P198, R62, O2sat:97%
• Chest  reduced breath sounds R base
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Chest xray: R base infiltrate

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1910
• First description (in western literature) of sickle cell disease by Chicago physician
James B. Herrick
• Patient from West Indies with anemia characterized by unusual red cells: “sickle shaped”
1927
• Hahn and Gillespie showed sickling of red cells was related to low oxygen

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1948
• Janet Watson (pediatric hematologist in New
York) noted newborn fetal hemoglobin lacked abnormal sickle hemoglobin seen in adults
• Linus Pauling and Harvey Itano showed that hemoglobin from patients with sickle cell disease is different from normals
• First disorder in which abnormality in protein known to be at fault

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1984
• B one marrow transplantation in a child with sickle cell disease produced the first reported cure
• Transplantation was performed to treat acute leukemia-child's sickle cell disease was cured as a side-event
1995
• Hydroxyurea became the first (and only) drug proven to prevent disease in the complications of sickle cell
Multicenter Study of Hydroxyurea in
Sickle Cell Anemia

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Hemoglobin - two pairs of nonidentical globin and polypeptide chains; each chain associated with one heme group
Four polypeptide chains (alpha, beta, gamma and delta) in the globin portion
• HbA - 2 alpha and 2 beta chains
• HbF - 2 alpha and 2 gamma chains
• HbA2 - 2 alpha and 2 delta chains
Heme group - iron containing pigment responsible for oxygen transport

Hemoglobin A

The chain of colored boxes represent the first eight amino acids in the beta chain of hemoglobin. The sixth position in the normal beta chain has glutamic acid , while sickle beta chain has two. valine . This is the sole difference between the

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1/400 African American infants
8% of African Americans are heterozygous carriers of the gene – they have trait
Also found in: African, Mediterranean,
Middle Eastern, Indian, or Caribbean ancestry
Pathology directly related to polymerization of deoxygenated sickle hemoglobin
• Distortion of erythrocyte morphology
• Reduced RBC life span
• Increased viscosity
• Episodes of vasoocculsion

 Antenatal diagnosis by amniocentesis or chorionic villus
DNA
 Hb S identified by electrophoresis and solubility testing
• Affected newborns express small quantities of Hb S – even with predominance of Hb F

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Clinical course:
•
• ischemic changes intermittent “crises”
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Anemia, increased reticulocyte count
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Splenomegaly in early childhood
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High risk of bacterial sepsis

OXYGEN SATURATION CURVES in (a) 41 normals and (b) 53 subjects with sickle cell anemia. For any given pO2, the saturation for
Hb SS cells is less than that for normal erythrocytes.
Resp Med 1988;9:291)
(Johnson CS,
Verdegem TV. Pulmonary complications of sickle cell disease. Semin

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Hemoglobin: 5-9 g/dl
Target cells, poikilocytes, sickled cells
Reticulocyte count 5-
15%
WBC count: 12-
15,000/mm 3
Platelet count increased
Increased LFT’s, bilirubin

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Surgical abdomen
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Rheumatic fever
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Rheumatoid arthritis
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Osteomyelitis
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Leukemia

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Priapism - GU tract infarction
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Retinopathy – sequestration of blood in conjunctival vessels; retinal hemorrhage
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Cholelithiasis - chronic hemolysis
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Osteonecrosis of femoral head

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Hematuria, hyposthenuria, renal failure - papillary necrosis
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Jaundice - hepatic infarct
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Stroke, seizures, weakness, sensory hearing loss - CNS ischemia
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Respiratory distress pulmonary infarction

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Maintain full immunization status
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Administer polyvalent pneumococcal vaccine (
Administer
vaccine
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Folic acid daily

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Prophylactic penicillin 4 mo- 5 yrs
(<5y: 125mg/12h; >5y:
250mg/12h)
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Aggressive ED approach to temperature >38.5
 C:
• laboratory studies (CBC, culture, UA and culture, chest x-ray)
• admission
• antibiotics

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Bacterial sepsis
• Other infections
Acute chest syndrome
Vasoocclusion crises
Splenic sequestration crises
Aplastic crises
Hemolytic crises
Treatment

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Impaired immunologic function, functional asplenia
Increased risk from:
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Greatest risk 6 months - 3 years of age

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Impaired immunologic function
• Loss of splenic activity
• Fulminant nature of illness
• Most dangerous period: 6m-3y (protective antibodies limited with diminished splenic function)
Risk of sepsis = 100X normal population
Streptococcus pneumoniae, h. influenza most common in young children
E. coli and salmonella most common in older children

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Differentiating the patient with viral illness vs serious bacterial illness (SBI) difficult
ONLY a blood culture can identify difference – MUST obtain rapidly and administer antibiotics
Clinical deterioration is VERY rapid
Treat for septic shock EARLY

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Emergence of penicillin resistant streptococcus pneumoniae
Rapid blood work and IV ceftriaxone or cefotaxime and vancomycin (if area of high resistance)
If not acutely ill on physical exam (no pallor, rales, increased spleen, rales) with guaranteed follow-up within 24H, may treat with ceftriaxone 50 mg/kg, otherwise admit

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Short stay outpatient unit also appropriate
If “low risk” for SBI, may give PO or
IV antibiotics and discharge….BUT
MUST SEE WITHIN 24 HRS for
FOLLOWUP
Older child with any fever…may not have high WBC and may not have high fever….BEWARE – admit for antibiotics and close observation

(Rogovik 2009)
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Retrospective chart review of 692 pediatric
SCD patients with or without fever from
2005-2007 in Toronto Sick Children’s
Hospital (inclusion in study limited to 530 with blood cultures)
77% of febrile children admitted; 7 positive cultures; 3 in febrile children
No s.pneumoniae species – “all identified microorganisms part of normal skin or oral flora and could be contaminants…”
• Thought to be due to 7-valent pneumococcal vaccine

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VERY difficult to diagnose clinically; similar to bone infarction
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Diagnostic tests prior to antibiotics: Gram stain and culture
• bone aspiration (osteomyelitis)
• joint aspiration (septic arthritis)
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Antibiotics

(Inusa 2010)
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Review of cases of H1N1 disease in patients with SS disease in children in London: April–
August 2009
21 positive cases among 2200 patients with
SCD; 19 were admitted; 11 needed blood transfusions due to falling Hg and ACS (10 patients had acute chest syndrome)
All successfully treated with oseltamivir

(Vichinsky 2000)
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Defined as a new infiltrate on a chest radiograph associated with one or more symptoms such as
• Fever
• Cough
• Sputum production
• Tachypnea
• Dyspnea
• New onset hypoxia

(Vichinsky 2000)
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Clinical and radiological similarity to bacterial pneumonia
• Fever, leukocytosis
• Pleuritic chest pain
• Pleural effusion
• Cough with purulent sputum
Clinical course is unique
• Multiple lobe involvement possible
• Duration of clinical illness and of radiologic clearing of infiltrates prolonged (10-12 days)

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Process may be initiated by
• Microbial infection
• In situ vaso-occlusion
• Fat embolism from ischemic/necrosis bone marrow
• Thomboembolism
?Activation of endothelium by oxygen radicals of erythrocytes or infection process that induces secretion of inflammatory cytokines

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Most cases are infectious origin
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Difficult to identify organism although more common organisms are
• Mycoplasma pneumoniae
• S pneumoniae
• Chlamydia trachomatis

(Johnson 2005)
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Fever > 38.5°C and cough most common – especially in children compared with adolescents
Tachypnea and bronchospasm more common in children
However – 35% of patients had normal PE ; “additional data support unreliability of the physical examination in the detection of ACS…”

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Symptoms: tachypnea, rales, ronchi, ?lobar consolidation
Workup: oxygen saturation, CBC, blood culture, chest x-ray (may be negative in 50% of cases)
Treatment:
• Start antibiotics early
• Initiate IV ampicillin or ceftriaxone (plus erythromycin in young child); consider streptococcus pneumoniae or Mycoplasma
• RBC transfusion or exchange transfusion for severe anemia (Hg < 5), hypoxia, radiographic evidence of rapidly progressive disease
• Therapy with steroids may prevent clinical deterioration in ACS

(Strouse 2008)
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Retrospective cohort study to examine risk factors for readmission and prolonged hospitalization at Johns Hopkins in patients
< 22 yrs of age 1998-2004
Identified 65 patients with 129 episodes of
ACS (mean age 12.5 yrs)
Readmission strongly associated with use of corticosteroid (OR 20, p<.005)
Suggest limited use of steroids

(Kumar 2010)
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Retrospective study of 63 patients with 78 episodes of ACS from 2005-2007 at SUNY
Downstate
“Asthma Regimen” of prednisone used
(2mg/kg/d max 80 mg in 2 divided doses for 5 days
15% of 53 children receiving steroids and
8% of the 25 children who did not receive steroids were readmitted (NS)
No significant readmission rate from steroids

(Sieff 2010)
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(Kikiska 2004)
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Increased incidence following abdominal surgery (15-20%)
ACS was associated with
• Age (young  vs old)
• Weight (lighter  over heavier)
• Operative blood loss (more > less)
• Lower final temperature

CAUSES OF ACUTE CHEST SYNDROME
1. Hb S–Related
* Direct consequences of Hb S
• Pulmonary vaso-occlusion (16.1%)
• Fat embolism from bone marrow ischemia/infarction (8.8%)
• Hypoventilation secondary to rib/sternal bone infarction or to narcotic use
• Pulmonary edema induced by narcotics or fluid overload
* Indirect consequences of Hb S
• Infection
Atypical bacterial
Chlamydia pneumoniae (7.2%)
Mycoplasma pneumoniae (6.6%)
Mycoplasma hominis (1.0%)

CAUSES OF ACUTE CHEST SYNDROME*
•Bacterial
•
•
Staphylococcus aureus
(1.8%)
•
, coagulase-positive
Streptococcus pneumoniae (1.6%)
Haemophilus influenzae (0.7%)
•Viral
•Respiratory syncytial virus (3.9%)
•Parvovirus B19 (1.5%)
•Rhinovirus (1.2%)
• 2. Unrelated to Hb S
•Fibrin thromboembolism
•Other common pulmonary diseases (eg, aspiration, trauma, asthma)
*Vichinsky et al., NEJM, 2000 and Johnson, Semin Resp
Med, 1988

POOR PROGNOSIS/POTENTIAL INDICATIONS FOR
EXCHANGE TRANSFUSION IN ACUTE CHEST
SYNDROME
(Vichinsky 2000, Johnson 1988, Fine 1997)
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Altered mental status and other acute neurologic findings
Persistent tachycardia >125/min
Persistent respiratory rate >30/min or increased work of breathing (nasal flaring, use of accessory muscles, sternal retractions)
Temperature >40°C
Hypotension compared with baseline

POOR PROGNOSIS/POTENTIAL INDICATIONS FOR
EXCHANGE TRANSFUSION IN ACUTE CHEST
SYNDROME
(Vichinsky 2000, Johnson 1988, Fine 1997)
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Arterial pH <7.35
Arterial oxygen saturation persistently <88%, despite aggressive ventilatory support
Serial decline in pulse oximetry or increasing
A-a gradient
Hemoglobin concentration falling by 2 g/dL or more
Platelet count <200,000/μL
Evidence for multiorgan failure
Pleural effusion
Progression to multilobe infiltrates

(Boyd 2004)
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Does asthma increase the risk of ACS in children with sickle cell disease?
Retrospective case control study
(cases: ACS, controls: no ACS)
Cases of physician diagnosed asthma
4 times (95% CI: 1.7, 9.5) more likely to develop ACS and longer hospitalization

(Sylvester 2006)
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Hypothesis: children with sickle cell disease hospitalized with ACS have poor lung function compared with those with SCD not hospitalized with ACS
Results
• Higher resistance, TLC and RV in ACS group
• No difference in PFTs pre/post bronchodilator therapy, but ACS group had lower FEV
25 and
FEF
75 pre and lower FEF
75 post
Conclusion – ACS hospitalized children had significant differences in PFT

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Infarction of bone, soft tissue, and viscera by sickled red cells
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Young children: usually painful crises involve extremities
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Older children/adolescents: head, chest, abdominal, back pain
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Intercurrent illness may precipitate crisis

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Acute sickle dactylitis
1 st manifestation of disease
Pain symmetrical swelling of hands and feet
Ischemic necrosis of small bones; rapidly expanding bone marrow chokes off blood supply
Radiographs helpful in chronic stage

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Occlusion of mesenteric vessels vs. appendicitis; pain may mimic acute surgical condition
Hepatic infarction - acute onset of jaundice and abdominal pain obstruction)
(similar to hepatitis, cholycystitis and biliary
GU Tract - renal papillary necrosis, priapism
• Antifibrinolytic drugs  -aminocaproic acid or tranexamic acid may cause ureteral clot

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Mild/Moderate Pain
• 1 ½ maintenance with oral or IV fluids or
D5½NS or D5¼NS
• Acetaminophen with or without codeine
• Admit if poor pain control, poor hydration status, or repeated ED visits
Severe Pain
• 1 ½ maintenance with oral or IV fluids or
D5½NS or D5¼NS
• Morphine 0.1-0.15 mg/kg IV
• Admit

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Spectrum of initial complaints: mild symptoms of TIA to seizures, coma, hemiparesis, death
Cortical infarction seen on MRI or CT
Immediately start 1½ - 2 volume exchange to reduce Hb S to < 30% of total Hb
• whole blood < 5 days old OR
• packed red cells < 5 days reconstituted with fresh frozen plasma
Preserve pre-transfused sample for red cell antigen identification

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Admit with severe pain or persistent erection
Hydration: 1½ - 2X maintenance for 24-48 hours with IV fluids D5½NS or D5¼NS
If swelling does not decrease, transfuse with red cells to raise Hb to 9-10g/dl
If no improvement, exchange transfusion to reduce Hb S to < 30% of total Hb
If no improvement, corporal aspiration or surgical procedure

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Symptoms: left upper quadrant pain, pallor, lethargy
Signs: hypotension, tachycardia, enlarged and firm spleen
Laboratory: severe anemia, thrombocytopenia, neutropenia, increased reticulocytes
Treatment: Immediate volume replacement, transfusion with packed red cells or whole blood

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Symptoms: progressive pallor, lethargy, may be caused by parvoviral infection
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Signs: absence of jaundice
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Laboratory: severe anemia, decreased reticulocytes
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Treatment: transfusion with packed red cells or whole blood

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Symptoms: viral/bacterial infection
Signs: sudden pallor, jaundice, scleral icterus
Laboratory: severe anemia, increased reticulocytes, active hemolysis
Treatment: rarely needs transfusion; await resolution of infection

(Sieff 2010)
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Fluids
• Primarily for vaso-occlusive crisis
• 1 ½ maintenance with oral or IV fluids or D5½NS or D5¼NS
Pain management
• Mild/moderate: oral medications acetaminophen with codeine or oxycodeine
• Severe: IV morphine or hydromorphine, patient controlled analgesia, NSAIDs

(Sieff 2010)
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Sepsis – antibiotics
• Due to emergence of resistant strains of s. pneumoniae, treat with 3 rd generation cephalosporin (cefotaxime or ceftriaxone) and vancomycin
• Watch for secondary organ damage due to sickling in presence of acidosis, stasis, and hypoxia – consider transfusion (packed RBC or exchange transfusions)
Acute chest syndrome – cover for appropriate organisms

(Roseff 2009)
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Transfusion
• Consider in patients with signs and symptoms of anemia
• Increases patient hemoglobin
• Dilutes Hg S with Hg A
•
RBC’s with Hg A - longer survival than Hg S
• Suppresses patient’s own erythropoiesis

(Roseff 2009)
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Simple transfusion (peripheral IV)
• Technical ease, low risk of exposure, dilution of Hg S
• Increases viscosity, risk of Fe overload
Exchange transfusion (automated machine)
• Rapid reduction in Hg S, no risk of Fe overload
• Requires large gauge catheter, expertise in special equipment, higher risk of exposure

(Roseff 2009)
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Indications for transfusion
• Aplastic crisis
• Hemolytic crisis (extremely rare)
• Splenic sequestration
• Priapism
• Presurgical prophylaxis
• Acute chest syndrome
• Stroke

(Sieff 2009, Steinberg 2010)
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Stem cell transplantation
Hydroxyurea
• Introduced 25 years ago based on ability to increase fetal hemoglobin (Hg F)
• Observational studies in children have shown benefits and safety
• Often used for maintenance therapy in patients with stroke
• In long term study (17.5 years f/u) mortality reduced in those treated with hydroxyurea

(Hunt 2010)
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30 day rate of return to acute care
• 10-17 yrs: 27.4%
• 18-30 yrs: 48.9%
Why the increase?
• Lack of insurance
• Poor follow-up contacts
• Too much reliance on emergency departments for ongoing care

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Chronic hemolytic anemia
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Crises: vasoocclusive (any organ, acute chest syndrome, stroke), hemolytic, sequestration, aplastic
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Watch for sepsis
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Continuity of care critical: immunizations, antibiotics

COMPETENCY BASED
OBJECTIVES
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Medical Knowledge
• knowledge about the established and evolving biomedical, clinical, and cognate (epidemiological and socialbehavioral) sciences and their application to patient care
•
Diagnosis, management of sickle cell disease

COMPETENCY BASED
OBJECTIVES
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Patient Care
• family centered patient care developmentally and age appropriate compassionate and effective for treatment of health care problems and promotion of health
•
Medical home for treatment of multispecialty disease

COMPETENCY BASED
OBJECTIVES
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Practice Based Learning
• investigation and evaluation of patient care, and the assimilation of scientific evidence
Communication Skills
• interpersonal and communication skills resulting in effective information exchange and learning with patients, families and professional associates

COMPETENCY BASED
OBJECTIVES
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System Based Practice
• understanding systems of health care organization, financing, and delivery, and the relationship of one’s local practice and these larger systems
Professionalism
• carrying out professional responsibilities, adherence to ethical principles, and sensitivity to diverse patient populations

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Vichinsky et al., NEJM, 2000
Fine et al, NEJM 1997
Johnson CS. The acute chest syndrome. Hematol
Oncol CLin N am 19 (2005) 857-879.
Sylvester KP et al. Impact of acute chest syndrome on lung function of children with sickle cell disease.
J Pediatr 2006;149:17-22.
Sylvester KP. Airway hyperresponsiveness and acute chest syndrome in children with sickle cell anemia. Pediatr Pulmonol 2007;42:272-276.
Sieff, CA. Hematologic emergencies. In Fleisher
Ludwig. Pediatric Emerg Med 6 th ed., Phila,
Lippincott. 2010

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Caboot JB and Allen JL. Pulmonary complications of sickle cell disease in children. Curr Opin Pediatr
2008;20:279-287.
Boyd JH et al. Asthma and acute chest in sickle cell disease. Pediatr Pulmonol 2004;38:229-232.
Kumar R et al. A short course of prednisone in the management of acute chest syndrome of sickle cell disease. J Pediatr Hematol Oncol 2010;32:e91-e94.
Strouse JJ et al. Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatr Blood
Cancer 2008;50:1006-1012.

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Inusa B et al. Pandemic influenza A (H1N1) virus infections in children with sickle cell disease. Blood
2010;115;110:2329-2340.
Rogovik AL et al. Bacterial blood cultures in children with sickle cell disease. Amer J Emerg Med 2010:28:511-514.
Roseff SD. Sickle cell disease: a review. Immunohematol
2009;25:67-74.
Steinberg et al. Risks and benefits of long term use of hydroxyurea in sickle cell anemia; a 17.5 year followup.
Am J Hematol 2010;85:403-408.
Hunt SE. Transition from pediatric to adult care for patients with sickle cell disease. JAMA 2010;304:408-
409.