Objectives

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Sickle cell disease 2009 Vaso-occlusive pain
Morey A. Blinder, M.D. Associate Professor of
Medicine and Pathology Immunology
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Hemoglobinopathy and Thalassemia Disorders of
the Globin Genes
Hgb A tetramer
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Peripheral Blood Smear
Sickle cell anemia
Normal
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Pathophysiology of sickle cell disease

• ?6 Glu Val
• Deoxy Hb S polymer forms with low O2,
• Causes irreversibly sickled cells
• Under a variety of circumstances, different
  organs are susceptible
• esp. bone, spleen, and lung

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Clinical Effects of Sickle Cell
AnemiaSusceptibility to infection

• Susceptible to infection
• Functional asplenia
• Infarcted tissue
• Numerous manipulations

Auto-splenectomy
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Clinical Effects of Sickle Cell AnemiaChronic
hemolytic anemia

• Cholelithiasis
• Calcium bilirubinate (radiopaque)
• 80 of patients gt30 years old
• Aplastic crisis
• Parvovirus B19
• Change in vascular tone

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Role of Nitric oxide (NO) in hemolytic anemia

• Produced in endothelial cells
• Vasodilator - counters the processes induced by
  hypoxia
• ? NO is low in sickle cell disease

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Depletion of NO in sickle cell anemia
Sickle cell disease Hemolysis Arginine NO
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Clinical Effects of Sickle Cell
AnemiaVaso-occlusion

• Vaso-occlusion
• Microinfarction

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Effect of Hgb polymerization on RBC membrane
Phosphotidyl serine (PS)
Lipid mediator may cause vascular damage and
endothelial adherence secretion of other
inflammatory mediators
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Vaso-occlusion Interaction of RBC, WBC and
Endothelium
Effects of RBCs sickle cells, membrane
phospholipids, adhesion molecules, cation
transporters Effects of endothelium Adhesion
molecules (Integrins, selectins) Effects of
inflammation Selectins, cytokines
expression Systemic effects Hemostasis, iron
overload, renal failure
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Sickle Cell Anemia Pathophysiologic features
Vaso-occlusion
Chronic hemolysis
Pulmonary hypertension Priapism Leg ulceration
Vasoocclusive crisis Acute chest
syndrome Avascular necrosis
Stroke
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Prevalence of Sickle Cell Related Complications
Van Beers et al., Haematologica 2008 93757-760
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Vaso-occlusion Sickle Cell Pain
EpisodesCharacteristics and Clinical
manifestations

• Average duration 5-7 days
• 30-50 of patients seen in ED are admitted
• Pain episodes account for 80-90 of admissions
• Average BJH hospital charges are 6,000/admission
• In 2004, 113,000 admissions cost 488 million
  (4,300/admission) 75 admissions were for
  adults, mostly for pain (Health Qual Life
  Outcomes 2006459)

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Sickle Cell Anemia Vaso-occlusive Events (Pain
Crisis)

• Precipitating factors
• Hypoxia
• Acidosis
• Fever
• Infection
• Dehydration
• Exposure to cold

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Causes of Pain Perceived factors

• Exposure to cold 34
• Emotional stress 10
• Physical exertion 7
• Pregnancy 5
• Alcohol consumption 4
• Not identified 40

Sergeant, G. et al., Brit J. Haemat 1994 87586.
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Sites of vaso-occlusive pain (n 183)
Site Frequency Bilateral Lumbar spine
49 Abdominal pain 32 Femur 30 28 Knees
21 68 Sternum 18 Ribs 18 47 Shoulder 1
8 53 Elbows 17 45 Tibia/fibula 15 57 H
umerus 12 44 Thoracic spine
12 Hips 11 48 All over 1
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Pain in Sickle Cell Disease
Definition Periodic, self-limited
episodes Known as Sickle cell crisis Occurs
in all age groups
Platt, O. Cooperative Study of Sickle Cell
Disease. N Engl J Med 1991 32511-16
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Sickle Cell Vaso-occlusion Approach to
Treatment
Hertz Nazaire, Port-au-Prince, Haiti
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Sickle Cell Anemia Painful Events Treatment
Principles

• Quantitative assessment of pain
• Verbal pain scale ( 0 - absent to 10 worst)
• Correct fluid/electrolyte abnormalities
• Decrease IV fluids/ switch to PO when stable
• Treat any underlying illness
• Opioid analgesics

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Opioids and sickle cell pain

• Proposed starting dose of opioids (Intermittent)
• Morphine sulfate 2-10 mg (0.05-0.1mg/kg) IV,IM or
  SQ q2-4 hours
• Proposed starting dose of opioids (PCA)
• Loading Morphine sulfate 2-10 mg IV by PCA with
  10 min lock out rate to control pain
• Bolus 20 of initial dose as bolus dose
• Convert 2/3 of infused hourly dose to basal
  rate
• Maintenance
• Taper PCA basal rate convert to long-acting oral
  agents

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Adjunctive therapy for sickle cell pain

• Diphenhydramine 25-50 mg PO or IV
• Hydroxyzine 25-50 mg PO or IM
• Anxiolytics
• Benzodiazepines
• Antiemetics (Prochloroperazine 5-10 mg PO or IM)
• Sedative
• Laxatives
• Magnesium citrate
• Lactulose
• Other agents
• Heating pad
• Non-pharmacologic approaches (biofeedback,
  relaxation or diversion)

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Opioids and sickle cell pain

• Short acting agents
• Codeine, hydrocodone or oxycodone
  acetominophen
• Meperidine
• Hydromorphone
• Morphine

• Long acting agents
• Morphine SR
• Oxycodone SR
• Methadone
• Fentanyl patch

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Vasoocclusion and Pain
Approach to Treatment Can we do better then
treating sickle cell patients like they have a
terminal malignancy?
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Clinical trials to reduce RBC, WBC and vascular
effects
Pre-clinical transgenic mouse models available
(
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Chronic and recurrent sickle cell painCauses
other than vaso-occlusion

• Acute exacerbation of chronic pain (avascular
  necrosis)
• Other bone and joint disease
• Iron overload syndrome
• Addiction and pseudo-addiction
• Secondary gain - the difficult patient

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Avascular necrosis (osteonecrosis) of bone
Blood vessel disruption (trauma) Intraluminal
obliteration (sickle cells) Increased marrow
pressure (fat)
Decreased intraosseus blood flow
Ischemia
Reversible
Irreversible Genetic factors? Critical
ischemia Heavy (weight bearing) loads
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Avascular necrosis (osteonecrosis)of the femoral
head

• Occurs in all forms of sickle cell disease
• Age- dependent
• 33-50 of patients by age 35
• Associated with severe pain worse with weight
  bearing
• Radiographic findings and clinical findings may
  not correlate

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Avascular necrosis of the femoral headPain
episodes is a major risk factor
Akinyoola, AL Int Ortho 2008 33923-6
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Staging Systems of Osteonecrosis of the Femoral
Head
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Osteonecrosis of the Femoral Head
Sclerotic changes
Crescent sign
Advanced osteonecrosis Irregularity of the
femoral head, flattening, joint space narrowing
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Sickle cell disease as a Cause of
Osteonecrosis of the Femoral Head
2590 patients followed over 5.6 years Risk
factors Number of pain crisis Higher Hct
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Natural history of asymptomatic osteonecrosis of
the femoral head in sickle cell disease
Time to onset of pain
Time to progression with collapse
Hernigou, P. J Bone and Joint Surgery. 2006
882565-2572
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Natural history of asymptomatic osteonecrosis of
the femoral head in sickle cell disease
Time to surgical intervention
Hernigou, P. J Bone and Joint Surgery. 2006
882565-2572
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Treatment of osteonecrosisof the femoral head

• Physical therapy
• Gait aid, home exercise regimen
• Core Decompression
• Insert guide pin into femoral head
• Trocar advanced into lesion and curettage and
  irrigation

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Treatment of osteonecrosisof the femoral head
total hip arthroplasty

• Hip arthroplasty
• Remove femoral head and cartilage
• Implant stemmed prosthesis into femoral canal
• Attach a femoral head prosthesis
• Ream existing cartilage and place polyethylene or
  metal liner into the cup to enable smooth motion

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Abdominal pain in sickle cell disease

• Right upper quadrant
• Acute cholecystitis
• Biliary colic
• Sickle cell hepatopathy
• Viral hepatitis
• Hepatic siderosis
• Other

• Left upper quadrant
• Splenic sequestration
• Splenic infarct
• Other

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Addiction and pseudo-addiction

• Addiction (abuse)
• Overwhelming involvement with obtaining and using
  mind-altering drug
• Pseudo-addiction
• Relief seeking behavior misidentified as
  addictive behavior

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The difficult patient withsickle cell disease

• Approximately 5 of patients account for 25-50
  of hospitalizations
• High use group has gt10 hospitalizations/year
• Hospital stay is longer (10 days vs. 6 days)
• Young, poor, unemployed, male
• Difficult interpersonal interactions
• May be associated with substance abuse
• Higher death rate

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Treating the difficult patient withsickle cell
disease

• Difficult and time consuming
• Guidelines
• Keep accurate account of opioids
• Set limits of consumption and time
• Designate specific provider to formulate plan in
  charge of plan
• Reduce opioids gradually
• Individualize care
• Consider detoxification/chemical dependency
  program
• Consider a contract

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Effect of Pain Rate on Survival of Patients
Platt, O. Cooperative Study of Sickle Cell
Disease. N Engl J Med 1991 32511-16
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SummaryPain and sickle cell anemia

• Sickle cell vaso-occlusive pain is the most
  common manifestation of sickle cell disease
• Morbidity and mortality from sickle cell anemia
  is directly related to pain episodes
• Advances in pain prevention and treatment have
  improved the quality of life of patients with
  sickle cell disease
• New approaches to pain prevention and treatment
  are likely to significantly help patients in the
  future

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Acute Chest Syndrome Clinical Findings

• Etiology - multifactorial
• Rib infarct causing splinting/atelectasis
• Pulmonary fat embolism
• Infection (mycoplasma, chlamydia, viral)
• Indistinguishable from pneumonia
• Pleuritic chest pain, fever, cough, tachypnea,
  hypoxia
• Laboratory diagnosis
• Worsening anemia
• Infiltrate on chest radiograph

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Acute chest syndrome Radiographic findings
Normal chest radiograph
Acute chest syndrome with bilateral opacities
more confluent in the right midlung zone
Restrepo C S et al. Radiographics 200727941-956
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Acute chest syndromeIncidence by hemoglobinopathy
Castro, et al. Blood 1994 84643
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Acute Chest Syndrome Prevention and Treatment

• High index of suspicion in hospitalized patient
• Incentive spirometry

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Acute Chest Syndrome Treatment

• Treat possible underlying infection (Cover
  community acquired and atypical infections)
• Bronchodilators and supplemental oxygen to
  correct hypoxia
• Adequate pain management Minimize splinting and
  avoid over-sedation
• Immediate RBC transfusion therapy
• Simple transfusion
• Exchange transfusion for
• Multiple lobes involved
• Rapidly progressing
• Worsening hypoxia

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Acute Chest Syndrome Outcome

• Complete recovery 91
• Weaned of supplemental O2 3.11.9 days
• Hospital discharge 5.42.3 days
• Chronic respiratory disease 3
• Death 6

Blood 1993
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Prevention of Sickle cell vaso-occlusive
complications

• Replacement of red blood cells
• Pharmacologic elevation of Hgb F
• Hydroxyurea
• Other - block sickling or sickle cell-
  endothelium interactions
• Polaxamer 188
• Gardos channel blockers

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Indications for RBC transfusionsin sickle cell
disease

• Indication Outcome
• Stroke Initial recovery
• decreased recurrence by 90
• Acute chest syndrome Rapid improvement
• Aplastic crisis May be life saving
• Pre-operative treatment Decrease post-operative
  
• (Hgb 10 g/dl) complications
• Symptomatic anemia Clinical improvement
• Splenic or hepatic sequestration Clinical
  improvement

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Treatment with Hydroxyurea

• Dose 15-35 mg/kg/day
• Dose-response in Hgb F
• Adverse effects
• Dose-limiting neutropenia
• Long-term effects uncertain
• Outcome
• Pain episodes decreased by gt 50
• Decreased incidence of acute chest syndrome
• Trend in improved survival

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Sickle cell diseaseEffect of hydroxyurea
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Effect of Hydroxyurea on Hgb F
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Hydroxyurea on the Frequency of painful Crises in
Sickle Cell Anemia
Charache, S. et al., N Engl J Med 1995
3321317-22
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Cumulative Mortality in Patients With Sickle Cell
Anemia in the MSH and in Follow-up
Steinberg, M. H. et al. JAMA 20032891645-1651.
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Summary

• Without any home runs the treatment of sickle
  cell disease has improved substantially (pain
  management, joint replacement surgery)
• Almost all patients live to adulthood and many
  complications may be prevented with hydroxyurea
• Vaso-occlusive pain and other complications are
  a major cause of morbidity in sickle cell anemia