Sickle Cell Anemia
Emergency management of acute
neurologic events in children
Dr. Mary-Lou O’Byrne
September 25, 2003
OUTLINE
• Case presentation
• Sickle Cell Anemia fundamentals
– Genetics
– Pathogenesis
– “Crises”
• Sickle Cell Disease Care Consortium
guidelines
• Therapies
• Prevention
CASE (C.F.)
• 6 ½ year old black Canadian with known
Sickle Cell Disease
• Well for 3 years
• Prior hx of splenic sequestration events
• Admitted to PLC x 3 in first 3 years of life
• Meds: Pen V and Folate
• Immunizations: UTD
Presentation (C.F.)
• Well at bedtime
• @ 23:00 woke crying with bilaterally
painful legs
• Mother is rubbing her legs when pt stops
crying, stiffens, and has a large emesis
• Generalized tonic seizure x 5 minutes
• EMS called
On arrival in E.D.
• Eyes closed but will open eyes to voice
commands
• c/o headache and abd pain
• Oriented to place and self
• PERL, marked nystagmus, diplopia on lateral
gazes w/ R>L lat rectus palsy
• Ataxia, unable to sit
• Vomiting with any mvmt
• Marked dysmetria
• DTR symmetric and brisk, Plantars downgoing
Exam cont’d
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Chest: clear, sats 85% in R/A, RR: 20
CVS: HR 60-80, murmur noted
ABD: liver 4 cm down, Spleen not palp
MSK: no tenderness, swelling or
erythema
Investigations
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CXR: mild cardiomegaly
Hgb 73
WBC 16.0 => 9 to 12 in hospital
Plt 529
CBG: pH 7.41 pCO2 38 pO2 191
Lytes N INR 1.2 PTT 23
Type and screen done
CT head done immediately and “normal”
Treatment in E.D.
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IV normal saline at maintenance
O2
ICU consulted
Admitted onto clusters w/in 2 hours of
arrival
Course in Hosp
• Resolution of most of her neurologic
findings within a few hours
• I phoned neurology after my shift and they
had not been consulted yet
• Hematology consulted later in day
• ECHO and ECG confirmed mild rt and left
ventricular enlargement and norm
ventricular func
• MRI/MRA done and abnormal
T2
Axial
MRI
MRI (FLAIR) vs. CT
Course in Hospital
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Exchange transfusion in ICU on fourth day
Sickle cells 84% to 34%
Residual left cerebellar signs on discharge
Follow up w/ brain injury team, hematology
for ‘possible’ chronic transfusion Rx
Sickle Cell Anemia
Normal RBC vs. Sickle Cells
Sickle Cell Anemia
• Hereditary hemoglobinopathy
– 8% of black Americans heterozygous for HbS
• 1910 Herrick first described ‘sickled’ cells
• Heterozygote (40% HbS) protects against
falciparum malaria
• African descent > Hispanic, Arabians, Indians and
whites
• 1973 life expectancy = 14.3 years
• 1994 life expectancy = 42 years men / 48 years
women
• Most American states screen all newborns
• (1:625 Afro-American births)
Sickle Cell Anemia
• Structurally abnormal hemoglobin
• Normally tetramer of 4 globin chains:
– 96%HbA (alpha2 beta2)
– 3% HbA2 (alpha2 delta2)
– 1% HbF (alpha2 gamma2)
• SCD: HbS is abnormal Beta chain
• Valine replaces glutamine on beta-globin
– Charge at site altered, allows polymerization of Hb
• Copolymerization w/ HbS>C>D etc
SCD – point mutation
Pathogenesis
• On deoxygenation HbS aggregates and
polymerizes (like viscous gel)
• Sickling is initially reversible w/ O2
• HbS returns to depolymerized state
• Recurrent sickling => memb damage and
irreversible sickling
• RBCs lose K+ & H2 O and gain Ca++
– Dehydrated cells
Pathogenesis - 2
• HbF (fetal = alpha2 gamma2) inhibits
polymerization of HbS
• Newborns protected until 5-6 months
• Coexistent alpha-thalassemia is protective
b/c it reduces the conc of Hb in a RBC
• Acidosis reduces O2 affinity of Hb and
deoxygenates HbS
• HbS causes:
1)chronic hemolytic anemia
2)occlusion of small blood vessels
==> ischemic tissue damage
Pathogenesis - 3
• RBC lasts 17 - 20 days
• % of sickled cells correlates to degree of
anemia/hemolysis
• No correlation b/w sickling and
microvascular events
• Non-sickled cells with memb damage
adhere to the endothelium of the
microvessels.
• Lowest O2 is in microcirculation
Pathogenesis - spleen
• Early childhood spleen enlarged w/
congestion, sickled RBC in splenic cords
and sinusoids
• Erythrostasis => thrombosis/infarction and
tissue hypoxia
• Scarring => shrinkage =>autosplenectomy
by adolescence
• By age 5y 95% have functional asplenia
Autosplenectomy
Immunodeficiency
• Impaired splenic function
• Defects in alternative complement pathway
impairs opsonization of encapsulated bacteria
• Increased susceptibility to Salmonella
osteomyelitis (bone necrosis)
• Pneumococci and Haemophilus influenzae
septicemia/meningitis most common causes of
death in SCD children
“Crises”
1.
2.
3.
4.
5.
6.
Dactylitis
Splenic sequestration
Aplastic anemia
Acute painful events
Acute chest syndrome
Neurological events
Dactylitis
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Common presentation of SCD in children <2 yrs
Swollen, tender hands and feet
Usually bilateral
Ischemia/necrosis of bone
Full resolution expected
• Humeral > femoral heads prone to necrosis in
older children/adults
>50% dev avascular necrosis of femoral head by 35yr
Dactylitis
Splenic sequestration
• 30% incidence in young children
• Rapid, severe worsening of anemia w/ good
reticulocytosis
• Enlarging, tender spleen
• Hypovolemic shock
• 15% mortality, 50% recurrent
• Often concurrent with viral illnesses
• Parents taught to palpate for spleen
• Rx: fluid resuscitation. + O2 + transfusion
Aplastic anemia
• Young children very sensitive to
Parvovirus B19 marrow suppression
(68%)
• Supraphysiologic oxygen decreases
erythropoietin production and decreases
retic w/in 2 days
• Supportive transfusions until retic return
Acute painful events
• Most frequent symptom after age 2 yrs
• Vaso-occlusion vs. shunting of blood flow
• Rx: hydration, O2 and aggressive narcotic
use. Avoid Demerol (incr dependence and
possible seizures)
• Cause usually not identified
• Peripheral/extremities in younger pts and
proximal (back, chest, abdomen) in adults
Acute Chest Syndrome
• s/s: dyspnea, cough, chest pain
• Occasionally: abd pain, fever, tachypnea, infiltrate on
CXR, leukocytosis
• Major danger is hypoxemia
• Affects 30% of SCD w/ Mortality: 10% (higher in adults)
• Vaso-occlusion or infection (S. pneum, H. influenzae,
Mycoplasma, Chlamydia, Legionella and viruses)
• Rx: oxygen, urgent partial exchange transfusion,
intubation, ?extracorporeal mb oxygenation, incentive
spirometry, +/- bronchodilators
• May follow febrile illness in children and painful event in
adults (w/ fat emboli)
Acute CNS events
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Overt CVA ~ 5% of children w/ SCD
Greatest incidence in 5-10 year olds
Silent infarcts in 17% before age 20
Correlates with:
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seizures
lower painful event rate
incr leukocyte ct >11.8
incr pocked RBC (>3.5% considered evid of splenic dysfunc)
SEN betaS globin gene haplotype
• Cooperative Study of Sickle Cell Disease in USA
• Followed patients for 20 years, from 6 months of age
– (Pediatrics March 1999)
Stroke
• Watershed perfusion areas in most occult
CVA
• Most strokes are ischemic, rarely
hemorrhagic
• Anterior vessels of Circle of Willis show
progressive narrowing w/ eventual
occlusion, collateral vessel dev and occ
moyamoya
(C.F.) MRA
Circle of Willis
SICKLE CELL DISEASE IN CHILDREN
AND ADOLESCENTS:
DIAGNOSIS, GUIDELINES FOR
COMPREHENSIVE CARE, AND CARE PATHS
AND PROTOCOLS FOR MANAGEMENT OF
ACUTE AND CHRONIC COMPLICATIONS*
Peter A. Lane, George R. Buchanan, John J. Hutter, Robert F. Austin,
Howard A. Britton, Zora R. Rogers, James R. Eckman, Michael R.
DeBaun, Winfred C. Wang, Prasad Mathew, Sarah Iden, Michael
Recht, Jesse D. Cohen, Ernest Frugé, Leanne Embry, Lewis Hsu,
Brigitta U. Mueller, Robert Goldsby, Charles T. Quinn, Marie Mann,
and Michele A. Lloyd-Puryear
for the Sickle Cell Disease Care Consortium**
*Revised at the Annual Meeting of the Sickle Cell Disease Care
Consortium, Sedona, AZ, November 10-12, 2001
ACUTE STROKE OR NEUROLOGIC EVENT IN CHILD WITH SICKLE CELL DISEASE
DEFINITION: Stroke, defined as an acute, clinically apparent neurological event, occurs in 8-11% of children with Hb SS. Common presenting symptoms and signs include
hemiparesis, monoparesis, aphasia or dysphasia, seizures, severe headache, cranial nerve palsy, stupor, and coma. Stroke may occur without warning as an isolated
event or may complicate other complications of sickle cell disease such as acute chest syndrome or aplastic crisis. Acute neurologic symptoms or signs require urgent
evaluation and treatment.
CONSULTS:
Hematology
Neurology
Physical Medicine and Rehabilitation
MONITORING:
1.
Rapid triage - urgent hematology consultation
2.
Hospitalize. Consider ICU admission and/or CR monitor first 24 hr and until stable.
3.
Vital signs, neuro checks q 2 hr.
4.
Record I & O, daily weight.
DIAGNOSTICS:
1.
Document duration of acute symptoms, any prior neurologic symptoms or trauma, and results of any previous CNS imaging studies (ie. CT, MRI, MRA, or TCD).
2.
Document details of the neurologic exam.
3.
Type and crossmatch for transfusion (see Medication/Treatment below). Consider requesting, if available, minor-antigen-matched, sickle-negative, and leukocytedepleted RBC.
4.
CBC, diff, platelet count, and reticulocyte count initially and as clinically indicated (compare with patient's baseline data).
5.
RBC minor-antigen phenotype if not previously documented.
6.
Consider screening coagulation profile.
7.
Blood and urine cultures if febrile.
8.
Electrolytes initially and daily until stable.
9.
MRI and MRA. If MRI/MRA not immediately available, CT without contrast to exclude intracranial hemorrhage with MRI/MRA later when available. Initiation of transfusion
therapy should not be delayed by arrangements for imaging studies.
10.
Consider CSF culture if febrile and no contraindication present.
FLUIDS, GENERAL:
1.
IV + PO@ 1 x maintenance
MEDICATION/TREATMENT:
1.
Partial exchange transfusion or erythrocytapheresis to Hb 10 gm/dl and Hb S (patient's RBC) 30% (may require transfusion medicine consult for erythrocytapheresis).
Remove femoral or central venous catheter as soon as possible after exchange transfusion to reduce risk of thrombosis.
2.
Simple transfusion with RBC to Hb approximately 10 gm/dl may be considered as an alternative to partial exchange transfusion for stable patients with Hb <6-7 gm/dl (do
not transfuse acutely to Hb >10 gm/dl, Hct >30%).
3.
Rx seizures if present.
4.
Rx increased intracranial pressure if present.
5.
02 by nasal cannula or face mask if needed to keep pulse ox 92% or  patient's baseline, if >92%. The etiology of a new or increasing supplemental 02 requirement
should be investigated.
6.
Consider hemoglobin electrophoresis after partial exchange transfusion or at discharge.
7.
Cefotaxime or cefuroxime 50 mg/kg IV q 8 h if febrile. Substitute clindamycin 10 mg/kg IV q 6 hr for known or suspected cephalosporin allergy. Strongly consider adding
vancomycin 10-15 mg/kg IV q 8 hr for severe febrile illness or for proven or suspected CNS infection.
8.
If applicable, continue prophylactic penicillin. Prophylactic penicillin should be discontinued while patient is receiving broad-spectrum antibiotics.
9.
See other Clinical Care Paths for pain, acute chest syndrome, acute splenic sequestration, aplastic crisis, priapism, if present.
DISCHARGE CRITERIA:
1.
Clinically and neurologically stable 24 hr. after transfusions.
2.
Afebrile 24 hr. with negative cultures for  24-48 hr. if applicable.
3.
Taking adequate oral fluids and able to take oral medication if applicable.
4.
Hematology, rehabilitation, and physical therapy follow-up organized.
5.
Initiate chronic transfusion program (see p. 27).
ACUTE STROKE OR
NEUROLOGIC EVENT IN CHILD
WITH SCD
DEFINITION: Stroke, defined as an acute,
clinically apparent neurological event, occurs in
8-11% of children with Hb SS. Common
presenting symptoms and signs include
hemiparesis, monoparesis, aphasia or
dysphasia, seizures, severe headache, cranial
nerve palsy, stupor, and coma. Stroke may
occur without warning as an isolated event or
may complicate other complications of sickle cell
disease such as acute chest syndrome or
aplastic crisis. Acute neurologic symptoms or
signs require urgent evaluation and treatment.
DIAGNOSTICS:
1. Document duration of acute symptoms, any prior neurologic symptoms or
trauma, and results of any previous CNS imaging studies (ie. CT, MRI,
MRA, or TCD).
2. Document details of the neurologic exam.
3. Type and crossmatch for transfusion (see Medication/Treatment below).
Consider requesting, if available, minor-antigen-matched, sickle-negative,
and leukocyte-depleted RBC.
4. CBC, diff, platelet count, and reticulocyte count initially and as clinically
indicated (compare with patient's baseline data).
5. RBC minor-antigen phenotype if not previously documented.
6. Consider screening coagulation profile.
7. Blood and urine cultures if febrile.
8. Electrolytes initially and daily until stable.
9. MRI and MRA. If MRI/MRA not immediately available, CT without contrast
to exclude intracranial hemorrhage with MRI/MRA later when available.
Initiation of transfusion therapy should not be delayed by arrangements for
imaging studies.
10. Consider CSF culture if febrile and no contraindication present
FLUIDS, GENERAL:
1. IV + PO@ 1 x maintenance
MONITORING:
1.Rapid triage - urgent hematology
consultation
2.Hospitalize. Consider ICU admission
and/or CR monitor first 24 hr and until
stable.
3.Vital signs, neuro checks q 2 hr.
4.Record I & O, daily weight.
MEDICATION/TREATMENT:
Partial exchange transfusion or erythrocytapheresis to
Hb 10 gm/dl and Hb S (patient's RBC) 30% (may
require transfusion medicine consult for
erythrocytapheresis). Remove femoral or central venous
catheter as soon as possible after exchange transfusion
to reduce risk of thrombosis.
2. Simple transfusion with RBC to Hb approximately 10
gm/dl may be considered as an alternative to partial
exchange transfusion for stable patients with Hb <6-7
gm/dl (do not transfuse acutely to Hb >10 gm/dl, Hct
>30%).
3. Rx seizures if present.
4. Rx increased intracranial pressure if present.
1.
MEDICATION/TREATMENT
5. 02 by nasal cannula or face mask if needed to keep pulse ox 92%
or  patient's baseline, if >92%. The etiology of a new or increasing
supplemental 02 requirement should be investigated.
6. Consider hemoglobin electrophoresis after partial exchange
transfusion or at discharge.
7. Cefotaxime or cefuroxime 50 mg/kg IV q 8 h if febrile. Substitute
clindamycin 10 mg/kg IV q 6 hr for known or suspected
cephalosporin allergy. Strongly consider adding vancomycin 10-15
mg/kg IV q 8 hr for severe febrile illness or for proven or suspected
CNS infection.
8. If applicable, continue prophylactic penicillin. Prophylactic
penicillin should be discontinued while patient is receiving broadspectrum antibiotics.
9. See other Clinical Care Paths for pain, acute chest syndrome, acute
splenic sequestration, aplastic crisis, priapism, if present.
DISCHARGE CRITERIA:
1. Clinically and neurologically stable 24 hr. after
transfusions.
2. Afebrile 24 hr. with negative cultures for  2448 hr. if applicable.
3. Taking adequate oral fluids and able to take oral
medication if applicable.
4. Hematology, rehabilitation, and physical therapy
follow-up organized.
5. Initiate chronic transfusion program (see p. 27).
CVA treatment
• Risk of recurrence is 70-90% and may be fatal
• Chronic monthly transfusion regimen to maintain HbS
<30%
– Reduces recurrence by 90%
– Continue until 18 years old
• Transcranial Doppler ultrasound to assess velocity of
flow in circle of Willis every year to screen children
• Not readily available for children here
• MRI/MRA
• If velocity >200 cm/sec, stroke risk is 10% per year
– start monthly transfusion therapy
– Reduces risk of stroke by 90%
» Recommendation from the Stroke Prevention in Sickle Cell
Anemia Trial (STOP)
Stroke Rx – Adult vs. Children
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CVA in adults to be treated as per non-SCD pts
t-PA can be considered
ASA and other antiplatelet drugs can be used
t-PA data in children not available
Most important in children to reverse the sickling
Expect much better recovery in children post
CVA
New Therapies
• Hydroxyurea
• Chronic Transfusion therapy
• Bone Marrow transplant
Hydroxyurea
• Increases fetal Hb (10 to 25%)
• Decreases mortality in adults
• Early information on children suggest safe
but efficacy data pending
Chronic Transfusion Rx
• Essential in strokes and Acute Chest Syndrome
• Risks:
– Iron overload
– Infection
– Alloimmunization (Afro-Amer don’t express many of
the minor red cell antigens present on Caucasian
RBC)
• Does not reverse ischemic damage
• Does not prevent avascular necrosis of hum/fem
Bone Marrow Transplant
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Very select population
<16 years old
With an HLA-matched sibling
5% mortality
Consider nonmyeloablative regime
– Stable stem cell chimera w/ phenotypic
overexpression of the healthy graft can
produce an asymptomatic pt
Prevention
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Early diagnosis
Vaccinations
Penicillin to age 5-6 years or longer
Folate
Transcranial Doppler (or MRI)
Chronic transfusion treatments
Parental education