Sickle Cell Disease

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Sickle Cell Disease ICU

• Muhammad Asim Rana

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• Sickle cell disease (SCD), an inherited disorder
  due to homozygosity for the abnormal hemoglobin,
  hemoglobin S (HbS).
• Hemoglobin S (HbS), results from the substitution
  of a valine for glutamic acid as the sixth amino
  acid of the beta globin chain, which produces a
  hemoglobin tetramer (alpha2/beta S2) that is
  poorly soluble when deoxygenated.

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• HbS polymerizes reversibly when deoxygenated to
  form a gelatinous network of fibrous polymers
  that stiffen the RBC membrane, increase
  viscosity, and cause dehydration due to potassium
  leakage and calcium influx .

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• These changes also produce the sickle shape.
• Sickled cells lose the pliability needed to
  traverse small capillaries.
• They possess altered sticky membranes (especially
  reticulocytes) that are abnormally adherent to
  the endothelium of small venules.

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Characteristic Sickle Shaped RBCs
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• These abnormalities provoke unpredictable
  episodes of microvascular vasoocclusion and
  premature RBC destruction (hemolytic anemia).
  Hemolysis occurs because the spleen destroys the
  abnormal RBC. The rigid adherent cells also clog
  small capillaries and venules, causing tissue
  ischemia, acute pain, and gradual end-organ
  damage. This venoocclusive component usually
  dominates the clinical course.

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Sickle Cell Syndromes

• Several sickle syndromes occur as the result of
  inheritance of HbS from one parent and another
  hemoglobinopathy, such as thalassemia or HbC
  from the other parent.
• The prototype disease, sickle cell anemia, is the
  homozygous state for HbS

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MAJOR CLINICAL MANIFESTATIONS
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• Anemia
• Episodes of ischemic pain (i.e., painful crises)
• Ischemic malfunction or frank infarction in the
• spleen,
• central nervous system,
• bones,
• liver,
• kidneys,
• retina
• lungs.

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Anemia

• Most patients with sickling syndromes suffer from
  hemolytic anemia, with hematocrits from 1530,
  and significant reticulocytosis. Anemia was once
  thought to exert protective effects against
  vasoocclusion by reducing blood viscosity.
  However, natural history and drug therapy trials
  suggest that an increase in the hematocrit and
  feedback inhibition of reticulocytosis might be
  beneficial, even at the expense of increased
  blood viscosity.

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Acute severe anemia 

• There are three settings in which an acute fall
  in hemoglobin concentration may be superimposed
  upon the chronic anemia
• 1.Splenic sequestration crisis
• 2.Aplastic crisis and
• 3.Hyperhemolytic crisis.

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Splenic sequestration crisis 

• With splenic sequestration crisis, vaso-occlusion
  within the spleen and splenic pooling of red
  cells produce a marked fall in hemoglobin
  concentration accompanied by persistent
  reticulocytosis and a rapidly enlarging spleen.
  There is a risk of hypovolemic shock,
  particularly in children. Although primarily
  associated with aplastic crisis, parvovirus B19
  infection may also be a risk factor for splenic
  sequestration.

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• Splenic sequestration crisis is associated with a
  10 to 15 percent mortality rate, occurring before
  transfusions can be given.
• Sequestration is recurrent in 50 percent of
  survivors as a result, splenectomy is usually
  recommended after the first acute event.

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Aplastic crisis 

• An aplastic crisis is characterized by the
  transient arrest of erythropoiesis, leading to
  abrupt reductions in hemoglobin concentration and
  red cell precursors in the bone marrow, and a
  markedly reduced number of reticulocytes in the
  peripheral blood (ie, reticulocytes lt1.0 percent
  and an absolute reticulocyte count lt10,000 per
  microL).

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Causes of aplasia

• Impaired erythropoiesis can be associated with a
  variety of infections. Most cases in children
  follow infection with human parvovirus B19, which
  specifically invades proliferating erythroid
  progenitors.

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• Other reported causes of transient aplasia are
  infections by Streptococcus pneumoniae,
  salmonella, streptococci, and Epstein-Barr virus.
  Affected patients require acute transfusion
  therapy. Reticulocytes typically reappear within
  2 to 14 days.

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Hyperhemolytic crisis

• Hyperhemolytic crisis refers to the sudden
  exacerbation of anemia with reticulocytosis. This
  complication is rare, its cause is unknown, and
  some experts doubt its existence. Most such cases
  probably reflect occult splenic sequestration or
  aplastic crisis detected during a period of
  resolving reticulocytosis.

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• However, some episodes have been documented in
  multiply-transfused patients, consistent with a
  delayed transfusion reaction in which the
  patient's own cells ("bystander hemolysis"), as
  well as the transfused cells, were being
  destroyed, perhaps by activated macrophages. A
  number of reports have noted response to
  treatment with IV immunoglobulin and/or
  corticosteroids.

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Vaso-occlusive crisis

• Vaso-occlusive phenomena and hemolysis are the
  clinical hallmarks of sickle cell disease (SCD).
• The polymerization of deoxy HbS is essential to
  vaso-occlusive phenomena.
• Polymerization alone does not account for the
  pathophysiology of SCD. Subsequent changes in red
  cell membrane structure and function, disordered
  cell volume control, and increased adherence to
  vascular endothelium also play an important role.

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Effects of vasoocclusion

• Acute painful episodes
• Multi organ failure
• Effect on growth and development
• Psychosocial effects
• Infection
• CVA
• Bone ischemia infarction

• Cardiac MI
• Dermatological---Leg ulcer
• Hepatobiliary
• Pulmonary
• Renal
• Retinopathy
• Effects on pregnancy
• Priaprism

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Acute painful episodes

• Episodes of acute pain, previously called sickle
  cell crisis, are the most common type of
  vasoocclusive event.
• Acute pain is the complication for which patients
  with sickle cell disease commonly seek medical
  attention, although some of these episodes are
  short-lived and are managed at home. The
  frequency of pain peaks between the ages of 19
  and 39 more frequent pain is associated with a
  higher mortality rate in patients over age 19.

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• Pain may be precipitated by events such as
  weather conditions (eg, high wind speed, low
  humidity, atmospheric pollutants), dehydration,
  infection, stress, menses, alcohol consumption,
  nocturnal hypoxemia, and rarely obstructive sleep
  apnea.However, the majority of painful episodes
  have no identifiable cause.

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• The episodes can affect any area of the body,
  with the back, chest, extremities, and abdomen
  being most commonly affected the pain severity
  can range from trivial to excruciating.
  Approximately one-half of episodes are
  accompanied by objective clinical signs such as
  fever, swelling, tenderness, tachypnea,
  hypertension, nausea, and vomiting.

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Multiorgan failure 

• The potentially fatal acute multiorgan failure
  syndrome is most often seen during severe pain
  episodes in patients with SCD. The pathogenesis
  of this syndrome in SCD is uncertain but may be
  reversed by prompt and aggressive exchange
  transfusion therapy.

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Infection 

• Infection is a major cause of morbidity and
  mortality in patients with SCD. Affected children
  are vulnerable to life-threatening infection as
  early as four months of age because of splenic
  dysfunction caused by sickling of the red cells
  within the spleen and the inability of the spleen
  to filter microorganisms from the blood stream.
  Splenic dysfunction is followed eventually by
  splenic infarction, usually by two to four years
  of age.

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• In the absence of normal splenic function, the
  patient is susceptible to overwhelming infection
  by encapsulated organisms, especially
  Streptococcus pneumoniae and Haemophilus
  influenzae. Dysfunctional IgG and IgM antibody
  responses, defects in alternative pathway
  fixation of complement, and opsonophagocytic
  dysfunction may also play a role in the
  predisposition to invasive infection.

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Renal menifestations

• The primary event appears to be sickling of
  erythrocytes in the vasa recta capillaries in the
  medulla, leading to microthrombotic infarction
  and extravasation of blood in the medulla.
  Sickling is promoted by the normal medullary
  environment low oxygen tension, low pH, and high
  osmolality (which pulls water out of the red
  cells, thereby increasing the concentration of
  hemoglobin S). The increased blood viscosity
  contributes to ischemia and infarction in the
  renal microcirculation.

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Renal Presentation

• Hematuria (due to papillary infarcts)
• Renal infarction and papillary necrosis
• Diminished concentrating ability
• Renal tubular acidosis 
• Abnormal proximal tubular function
• Acute renal failure 
• Progressive renal failure and proteinuria 
• Renal medullary carcinoma 
• Urinary tract infection
• Blood pressure

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Cerebrovascular Accidents

• A cerebrovascular accident (CVA) is a leading
  cause of death in both children and adults with
  SCD. The reported age-adjusted incidence is 0.61
  to 0.76 per 100 patient years (ie, 0.61 to 0.76
  percent per year) during the first 20 years of
  life. This rate is approximately 300 times higher
  than that seen in children without SCD (0.0023
  per 100 patient years)

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Factors other than SCD in CVA

• Apart from sludging and occlusion of small
  vessels by rigid red cells, which produces
  ischemia in the cerebral microcirculation, other
  factors are
• Chronic anemia may reduce cerebrovascular reserve
  
• Flow-related hemodynamic injury to the arterial
  endothelium, which may promote adherence of
  sickle cells to the endothelium, producing
  further endothelial injury
• Development of moyamoya vessels
• A hypercoagulable state
• HLA-related susceptibility for stroke

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Acute chest syndrome 

• The acute chest syndrome (ACS) is the most common
  form of acute pulmonary disease in patients with
  SCD, occurring in almost one-half of patients. It
  is the most frequently reported cause of death in
  adults, and is a risk factor for early mortality.

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• A working definition of ACS is the presence of
  the following signs and symptoms in a patient
  with sickle cell disease.
• 1.Presence of a new pulmonary infiltrate, not
  due to atelectasis,
• 2.Involving at least one complete lung
  segment
• 3.Chest pain
• 4.Temperature gt38.5ºC
• 5.Tachypnea, wheezing, or cough

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Etiology

• The precise etiology of ACS is unclear. Causes
  can be listed as
• 1. Unknown cause
• 2. Pulmonary infarction
• 3.Fat embolism
• 4.Chlamydia pneumoniae infection
• 5.Mycoplasma pneumoniae infection
• 6.Viral infection
• 7.Mixed infections
• 8.Other pathogens

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Clinical findings 

• Patients with ACS initially present with fever,
  chest and/or extremity pain, dyspnea, and
  nonproductive cough. Examination of the chest may
  reveal local tenderness over the ribs or sternum
  findings of pulmonary consolidation may also be
  noted.

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symptoms

• Fever
• Cough
• Tachypnea
• Chest pain
• Shortness of breath
• Arm and leg pain
• Abdominal pain
• Rib or sternal pain
• Wheezing

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Common laboratory findings include

• Leukocytosis
• Thrombocytopenia or thrombocytosis
• Falling hemoglobin concentration
• Elevations in lactate dehydrogenase and
• Bilirubin levels

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• Although the chest radiograph may be normal in
  one-third of cases on admission, most patients
  will develop lower lobe infiltrates (which are
  bilateral in one-third). Pleural effusions are
  present in 25 to 35 percent of patients.

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Diagnosis

• No current laboratory or radiographic finding
  permits the differentiation of ACS from other
  acute pulmonary manifestations of SCD, including
  pneumonia and infarction.
• The finding of pulmonary infiltrate should be
  treated as infectious pneumonia (assume both are
  present) until proven otherwise.

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• Cytologic samples obtained via bronchoalveolar
  lavage or sputum induction may reveal alveolar
  macrophages containing fat droplets following
  pulmonary fat embolism, but the diagnostic and
  prognostic value of this finding in patients with
  ACS has not been established.

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• The differentiation of pulmonary infarction due
  to thromboembolic phenomena from ACS remains
  problematic. Difficulties in establishing the
  diagnosis of pulmonary infarction include the
  lack of evidence for deep venous thrombosis in
  the majority of patients, abnormal
  ventilation-perfusion scans in patients with SCD
  at baseline, and the inability to safely perform
  contrast studies in these patients because of the
  possible association with further sickling.

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Urgent Investigations

• Steady state Hb Hb electrophoresis
• CBC, Retics peripheral film
• Blood Cultures
• Urine microscopy cultures
• CXR
• UE
• Blood group antibody screening
• ABGs Pulse oxymetry

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ACUTE MANAGEMENT

• Given the broad diagnostic criteria, the clinical
  severity of ACS is also broad. However, even the
  diagnosis of a clinically mild case of ACS should
  prompt admission for close monitoring of
  progressive pulmonary changes and escalating
  severity because the clinical status of these
  patients can quickly deteriorate if the
  underlying pulmonary insult is not reversed.

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Therapeutic interventions 

• The goals of therapy are to correct underlying
  factors that contribute to deoxygenation of
  hemoglobin S (Hgb S) that leads to sickling of
  the red blood cell and ischemia and injury to
  lung.

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Fluid 

• If dehydration is present, it should be corrected
  as hypovolemia can contribute to increase
  sickling. Hypovolemia should be corrected with
  the administration of isotonic solution.
• Once it is corrected, euvolemia should be
  maintained using hypotonic oral and intravenous
  fluids with the rate of fluid administration
  adjusted to the clinical status and needs of the
  patient (eg, presence of fever).

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• Overhydration or rapid hydration should be
  avoided because they may result in pulmonary
  edema or congestive heart failure. Furosemide may
  be helpful if fluid overload is suspected.
  Weights should be monitored daily along with
  intake/output for assessment of the fluid status
  and management of the patient.

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Pain control 

• Adequate analgesia of spine, thoracic, and
  abdominal pain is important to prevent
  hypoventilation.
• The optimal approach to the treatment of the
  painful episode is three-fold
• Initiate treatment within 15 to 30 minutes after
  arrival in the emergency department or ICU.
• Administer an effective initial dose of
  medication, based whenever possible on the
  individual's prior experience with analgesics
• Reevaluate the patient's pain status 15 to 30
  minutes after the initial dose, with repeated
  doses given as often as every 15 to 30 minutes
  until the patient's pain is significantly
  improved.

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Opiates 

• Morphine 5-25 mg IM at 2-4 hrs intervals, or by
  continuous IV infusion, give a loading dose of 10
  mg ( 5 mg if less than 50 kg) followed by
  infusion of 150 mcg/kg/hr or--
• Diamorphine 5-25mg SC at 2-4 hrs or--
• Pethidine 50-150 mg at 4-6 hrs
• Meperidine is NOT recommended for the treatment
  of painful episodes of SCD because multiple doses
  are associated with accumulation of normeperidine
  along with central nervous system toxicity,
  including but not limited to mild twitching,
  multifocal clonus, and seizures.

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Newer approaches 

• Ketorolac is a potent nonsteroidal
  antiinflammatory drug that can be given by
  injection or orally. As a single parenteral agent
  it provides analgesia superior to parenteral
  meperidine, causes no respiratory depression, and
  is especially effective for relieving bone pain
  in patients with SCD

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• Tramadol is a centrally acting analgesic that is
  administered orally. It binds to the mu-opioid
  receptor, inhibits norepinephrine and serotonin
  reuptake, and induces minimal respiratory
  depression.

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• Epidural analgesia  Epidural analgesia is a
  useful adjunct for the treatment of severe
  painful episodes unresponsive to the usual
  therapies.

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• Methylprednisolone  The efficacy of
  methylprednisolone, given as an intravenous
  infusion of 15 mg/kg to a total dose of 1000 mg
  on admission and again one day later, was
  evaluated in a randomized trial of 36 patients.
  Although pain relief was superior to placebo
  (mean duration of analgesia 41 versus 71 hours),
  there was an unacceptably high rate of rebound
  pain after discontinuation of therapy.

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• Poloxamer 188  Poloxamer an experimental agent,
  is an artificial nonionic surfactant that reduces
  sickle erythrocyte adherence to the endothelium.
  In a randomized trial in 50 patients with acute
  painful episodes, poloxamer 188 given as a 48
  hour infusion reduced the total opioid
  requirement, the duration of pain, and the pain
  intensity.

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Respiratory support 

• Respiratory support including oxygen
  supplementation should be provided to maintain
  arterial oxygen saturation 92 percent.
• Incentive spirometry, preferably supervised by a
  clinical worker, should be employed at least
  every two hours to prevent atelectasis from
  hypoventilation.

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• For patients with poor respiratory effort or
  rising oxygen requirements, the use of positive
  pressure ventilation devices such as nasal mask
  continuous positive airway pressure (CPAP) or
  bilevel positive airway pressure (BiPAP) may be
  useful.
• For patients with respiratory failure and acute
  respiratory distress syndrome (ARDS),
  conventional or high-frequency oscillatory
  mechanical ventilation can be used.

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Other respiratory interventions include

• Inhaled nitric oxide
• Extra corporeal membrane oxygenation
• Bronchoalveolar lavage
• (Bronchoscopy with bronchoalveolar lavage
  (BAL), usually reserved for patients with severe
  or progressive infiltrates, provides both
  diagnostic and therapeutic benefits. Bronchial
  samples can be examined for lipid content in
  alveolar macrophage as evidence for pulmonary fat
  embolism and also sent for culture. In intubated
  patients, bronchoscopy with suction and removal
  of bronchial casts has been reported to improve
  patient ventilation)

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Infection 

• Broad spectrum empiric coverage with a third
  generation cephalosporin (eg, cefotaxime or
  ceftriaxone) for bacterial coverage and a
  macrolide (eg, azithromycin or erythromycin) for
  coverage of atypical organisms (such as
  mycoplasma and chlamydia) should be initiated
  immediately on admission.

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Transfusion

• In patients with ACS, transfusion therapy should
  be considered early in the course of the disease.
• Simple Transfusion
• Exchange Transfusion

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Simple transfusion

• The goal of simple transfusion is to increase the
  hematocrit (Hct) to 30 percent or hemoglobin
  (Hgb) to 11 g/dL.
• 1. To improve oxygenation
• 2.For accentuated anemia
• 3.For patients with clinical or radiological
  progression of disease but not impending
  respiratory failure.
• 4.For patients in whom exchange transfusion
  will be delayed. Simple transfusions may be used
  to temporize the clinical situation until the
  exchange transfusion can be performed.

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Exchange transfusion

• Neurological involvement
• Lung involvement (PaO2lt9kPa with FiO2gt60)
• Rapidly falling haemoglobin
• Priaprism

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Others

• Fever control
• Corticosteroids

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Complications

• Neurologic events may complicate the course of
  ACS, particularly when patients have severe
  pulmonary disease and/or respiratory failure,
  including
• Reversible posterior leukoencephalopathy
  syndrome
• Silent cerebral infarcts
• Acute necrotizing encephalitis

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LONG-TERM MANAGEMENT

• The goal of chronic management of the child with
  a history of ACS is to prevent recurrence and
  monitor for long-term consequences of ACS.
• Infection prevention 
• Pulmonary 
• Hematologic 

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Infection prevention

• The risk of infection, which can be a trigger for
  ACS, can be decreased by
• Prophylactic antibiotics
• Complete immunization for Streptococcus
  pneumoniae, Haemophilus influenzae type B,
  hepatitis B virus, and influenza

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Pulmonary

• The pulmonary status of all patients with SCD
  should be monitored with periodic checks of
  resting oxygen concentration by pulse oximetry
  and assessment for reactive airway disease.
• All episodes of reactive airway disease should be
  recognized early and treated promptly with
  bronchodilator therapy.

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Hematologic 

• Therapy aimed at decreasing the polymerization of
  Hgb S and sickling include
• Hydroxyurea Hydroxyurea has been shown to
  decrease the frequency of ACS. Hydroxyurea
  reduced the incidence of ACS by 40 percent in
  adult patients
• Transfusion Transfusion therapy is an
  effective intervention for the prevention of
  recurrent ACS
• Hematopoietic cell transplantation For
  patients who have experienced multiple ACS events
  and who have an HLA-matched sibling donor,
  hematopoietic cell transplantation is an accepted
  alternative, with a better than 80 percent
  success rate

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If no questions

• Thank you very much