Hospital Management of
Sickle Cell
“Playing Fireman…..”
Brad Lewis
SFGH
…bloods so mad, feels like coagulatin’….
Berry McGuire (Eve of Destruction)
A pint of sweat will save a gallon of blood
Gen. George Patton
Case #1
A Pain in the ……
• 28yo woman with SSD presents with
bilateral thigh and low back pain
– Stable sickle cell disease without Cx in past
– Long history of long hospital stays
• No recreational drugs, modest narcotic use between
hospitalizations
– Well prior to abrupt onset pain
– Presents to ER
Case #1
• IV Dilaudid
– Pt had no preference
– But wanted IV benedryl with each injection for
pruritus
• Meds: Vicoden, Folate
• PE unrevealing
• Labs
– WBC 14,000, no bands, Plt 473,000
– Hgb 8.3 MCV 88, Retic 240
Question #1
3.5 Wks Later Still Inpt, Now What?
• 1. Frustrating, but not unusual
• 2. Dilaudid is not optimal, change to MS
and Effexor
• 3. Look for the cause of the pain
• 4. Psychosocial factors are often
underestimated
Question #1
3.5 Wks Later Still Inpt, Now What?
• 1. Frustrating, but not unusual
• 2. Dilaudid is not optimal, change to MS
and Effexor
• 3. Look for the cause of the pain
• 4. Psychosocial factors are often
underestimated
What is Sickle Cell?
EM from U Chic
Mechanisms of Sickle Pathology
PMN Induced
Ischemic Endothelial
Damage
NO
Reticulocyte
Adherence
Integrin
vWF
VCAM
TNF
IL-1
Thrombosis
Mechanical Obstruction
NO and Thrombosis
• NO binds to Free Hgb/Arginine destroyed
by Arginase
• Vasodilator
• Inhibits Platelet Adhesion
• Decrease Endothelial Adhesion Molecules
– Inflammatory Activation of Endothelium
• Decreased Release of Vasoconstrictors
• Decreased Tissue Factor Expression
Causes of VOC in Sickle Cell
• Dehydration
– Fluids (duh!)
• ETOH
– Illness
– Travel
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•
•
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Infection / Inflammation
Hypoxia ??? (not sleep apnea)
Local Problems
Increased Time in distal circulation
– CHF, viscosity, RBC rigidity, Hemoglobin level
• Hemolysis
• Acidemia
• Psycho-social
Phenotypic Variability
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All Begin with Same Mutation (SS = SB0)
Alpha Thalassemia
Haplotype
Fetal Hgb (? >5%)
– interfere with polymerization
– dilution?
– Haplotype Dependence??
• Other Polymorphisms
– NO metabolism
Chronic Pain In Sickle Cell
• Structural
– AVN
– Old Infarctions
• Neuropathic
– Chronic Pain related
– Sickle Cell Related
• Inflammation Related
– Analgesia related
• Behavioral/Learned
– Patient
– Physician
• Non-Sickle Cell
Pain Management in SSD
• Acute vs. Chronic Pain
• Avoid Undertreatment and SLOW Tx
– No Demerol, IV Benedryl
– PCA?
– Ancillary meds
• NSAID, Sedatives/Sleeper, Tylenol, Lido Patch
– IV to Equi-analgesic PO
• Expect 2-5 days
– ?Precipitant if longer
– Transfusions??
Case #2
• 23yo AA male with well-known SS Disease
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–
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–
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Frequent VOC with prolonged admissions
Hx of incarceration for drug offenses
Now c/o calf/leg pain, chest pain and malaise
“Nothing different” to precipitate “usual” attack
PE:
• VS stable
• Lungs clear, Cardiac normal
• Calf tenderness
Case #2
• Hgb 7.5
– Retic Count 280
• WBC 20,000
– 70% PMN, 10% Bands
• Day 2, Calf and Chest pain worsen, RR 26,
Temp 38
– Utz Reveals popliteal DVT
Question #2
What Should We Do Now?
• 1. Improve pain management, consider
sedatives and anti-depressants
• 2. Look for the serious—CT angio,
culture/Rx for pneumonia
• 3. Time will tell-take a deep breath and
suggest patient do the same
• 4. This is Acute Chest, start treatment now
Question #2
What Should We Do Now?
• 1. Improve pain management, consider
sedatives and anti-depressants
• 2. Look for the serious—CT angio, culture
for pneumonia
• 3. Time will tell-take a deep breath and
suggest patient do the same
• 4. This is Acute Chest, start
treatment now
Case #2
• Venous Utz + for popliteal DVT>>>Lovenox
– With trepidation
• Chest pain worsens, RR 26, Temp 38
– High Res CT negative for PE but infiltrates
– Ceftriaxone, Fluids, Aggressive O2,
Exchange Transfusion considered
• 2 Hours Later, Pulmonary status worsens
– MOSF
• Pt Dies 2 hours later after unsuccessful Code
Death in SSD
• Median Age at Death= 42-48
• 60% of patients will die within 24hrs of
admission, usu. presenting with pain
Infection
Acute Chest
Thrombosis
Renal Failure
Pulmonary HTN
What Causes Sickling?
• Deoxygenation
• Acidosis
• Inflammation
– No GCSF
• Slow Flow
• Increased MCHC
– Dehydration
Acute Chest Physiology
Acute Chest Physiology
Sickling
NO depletion
Inflammation
local
systemic
Endothelial Activation
sPLA2
Paul, R; Euro J of Haem 87 (191–207)
Acute Chest Syndrome
• Dx:
– Chest Pain-may be chest wall
• Role of rib infarction?
– Fever
– Cough/ Wheezing
– Hypoxia
One of These
– CXR nl in 30% initially
– Often follows VOC
• Occ. Falling hgb
• High Index of Suspicion
– >50% missed clinically
– Because of catastrophic severity (10% Adults Die)
Vichinsky, E. P. et al. NEJM 2000;342:1855-1865
Etiology of ACS
• Fat Emboli
– Inflammation
– Occlusion
• Sickling / Occlusion
– Hypoxia
– Inflammation
• Infection
• Thromboembolic
– Difficult to evaluate
Risk Factors for ACS
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•
•
•
•
•
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Younger Age for occurrence/ older for Cx
SS or S-beta0
AVN
Previous Hx of pulmonary events
High Hemoglobin
High PMN
Low Hgb F
?Secretary PhospholipaseA2
Risk Factors for Bad Outcome
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•
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Age
Pre-existing heart failure/ renal failure
Multi-lobe or effusion
Platelet count <200,000
Neurologic event
Fever?
ACS Treatment
– Antibiotics (Strep, H. flu, Mycoplasma, Chlamydia )
– Oxygen
• 13% on ventilators/ 80% recover
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–
–
–
Bronchodilators (20% w/o wheezing had improvement)
Fluid (carefully)
Analgesia
Exchange Transfusion
• Simple Tx if Hct <30 at end??
• Exchange if acute, target Hgb SS<30%
– 5-10% will die overall
• 7x RR of CVA during next 2 weeks (role of fat emboli?)
Oxygen Delivery
O2 Delivery vs. Hgb
SS
10
Nl
15
Hemoglobin
2nd
Polycythemia
20
Role of Exchange Transfusion
• Acute Transfusion Therapy
–
–
–
–
–
–
ACS
CVA
MOSF
RUQ Syndrome
Priapism
Major Surg w/ Comorbidities
• Chronic Exchange Transfusions
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–
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–
–
Recurrent ACS
CVA
Leg Ulcers
Hypoxia
??Pain
Question #3
Pt with acute chest, exchange
transfused. 3d later with fever,
worsening pain, anemia. What now?
• 1. Fever in splenectomized pt, begin broadspectrum Abx
• 2. Work-up for a transfusion reaction
• 3. Repeat exchange transfusion
• 4. Fever, pain, anemia >>worsening sickle VOC
Question #3
Pt with acute chest, exchange
transfused. 3d later with fever,
worsening pain, anemia. What now?
• 1. Fever in splenectomized pt, begin broadspectrum Abx
• 2. Work-up for a transfusion reaction
• 3. Repeat exchange transfusion
• 4. Fever, pain, anemia >>worsening sickle VOC
Delayed Transfusion Rxn
• 30-50% SS pts with alloab, 4-8% DHTRs
– Crude estimate 0.1% of non-SSD recipients
• HLA, Chronic inflammation
– Caucasian Donors (antigens E, C, Kell, Fya, Fyb, and Jkb)
• Presentation (VOC)
– Drop in Hct 3-20d after transfusion
• Increase in Hgb A in SSD
– Reticulocytopenia or Reticulocytosis (hyperhemolysis)
– LDH, Bili increased often, DIC in severe cases
– Positive DAT ? / Crossmatch ?
• Initial negative DAT in some
• Subsequent negative DAT if donor cells destroyed
34
Autoimmune Hemolysis post-Tx
• DAT Positive (Like Delayed Tx Reaction)
• Often missed
– 10% Sickle Cell Patients
• “I’m worse than before the transfusion”
• Often with VOC, etc
• Increased risk with increased transfusion burden
– May persist for 4-6 mo after Transfusion
• ??Bystander, immune dysregulation
– Complement Activation?
Question #4
Sickle Cell Pt with VOC: WBC
18, Stable Hgb-7.5, LDH-300,
Bili 2.3. What now?
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•
•
•
1. Usual- fluids, O2, IV Dilaudid
2. Begin Antibiotics for possible infection
3. Should have been sent home from the ER
4. I won’t answer without a retic count
Evaluating Hemolysis
The Bucket with The Hole
Evaluating Hemolysis
The Bucket with The Hole
Aplastic Crisis
Cherchez le ‘tics
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Parvovirus B19
Infection
Drug
“Chronic” Disease Anemia
All the usual causes of marrow
failure
– folate, B12
– Myeloma if older
– Etc.
An Approach to Anemia
Anemia
Retic Hi
Retic Low
MCV Lo
MCV Nl
MCV Hi
An Approach to Anemia
Anemia
Retic Hi
Loss
Retic Low
Destruction MCV Lo
Tissue Intrinsic
On Floor Extrinsic
Occult Splenic
Mechanical
Recovery
Iron
(Lead)
Thal
Frags
MCV Nl
Chronic Disease
Renal
Mixed
Mild/Treated
Early
Transfused
Endocrine
Intrinsic BM
Dilution
MCV Hi
B12
Folate
Liver
ETOH
Thyroid
Toxic
MDS
Anemia
Retic Hi
Loss
Destruction MCV Lo
Retic Low
MCV Nl
MCV Hi
Tissue Intrinsic
On Floor
Hgb’opathy
Occult
Enzymopathy
Membrane
HS
PNH
Extrinsic
Splenic
Mechanical
Recovery
An Approach to Anemia
Anemia
Retic Hi
Loss
Destruction MCV Lo
Tissue Intrinsic
On Floor Extrinsic
Occult
AIHA
Recovery
cold
warm
Drug/Toxins
Sepsis
Burns
Splenic/Hepatic
Mechanical
MAHA
Retic Low
MCV Nl
MCV Hi
Hydroxyurea
• Increases Hgb F production
– Recovery from cytotoxicity?
– Anti-inflammatory Effects? NO production?
• Decreased VOC, Acute Chest, Transfusions
– In 60%
– Why variable response?
• 40% Decreased Mortality
• S/E
– Cytopenias
– Rash
– Hepatotoxicity
Erythropoietin
• Small further increase Hgb F
• Increased Hgb in anemic
– Inappropriately low epo levels in SSD
– Renal failure
– CDA