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Sickle Cell Anemia Emergency management of acute neurologic events in children Dr. Mary-Lou O’Byrne September 25, 2003.

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Presentation on theme: "Sickle Cell Anemia Emergency management of acute neurologic events in children Dr. Mary-Lou O’Byrne September 25, 2003."— Presentation transcript:

1 Sickle Cell Anemia Emergency management of acute neurologic events in children Dr. Mary-Lou O’Byrne September 25, 2003

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3 OUTLINE Case presentation Sickle Cell Anemia fundamentals –Genetics –Pathogenesis –“Crises” Sickle Cell Disease Care Consortium guidelines Therapies Prevention

4 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

5 Presentation (C.F.) Well at 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

6 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

7 Exam cont’d 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

8 Investigations CXR: mild cardiomegaly Hgb 73 WBC 16.0 => 9 to 12 in hospital Plt 529 CBG: pH 7.41 pCO 2 38 pO Lytes N INR 1.2 PTT 23 Type and screen done CT head done immediately and “normal”

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12 Treatment in E.D. IV normal saline at maintenance O 2 ICU consulted Admitted onto clusters w/in 2 hours of arrival

13 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

14 T2 Axial MRI

15 MRI (FLAIR) vs. CT

16 Course in Hospital 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

17 Sickle Cell Anemia

18 Normal RBC vs. Sickle Cells

19 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)

20 Sickle Cell Anemia Structurally abnormal hemoglobin Normally tetramer of 4 globin chains: –96%HbA (alpha2 beta2) –3% HbA 2 (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

21 SCD – point mutation

22 Pathogenesis On deoxygenation HbS aggregates and polymerizes (like viscous gel) Sickling is initially reversible w/ O 2 HbS returns to depolymerized state Recurrent sickling => memb damage and irreversible sickling RBCs lose K+ & H 2 O and gain Ca++ –Dehydrated cells

23 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 O 2 affinity of Hb and deoxygenates HbS HbS causes: 1)chronic hemolytic anemia 2)occlusion of small blood vessels ==> ischemic tissue damage

24 Pathogenesis - 3 RBC lasts 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 O 2 is in microcirculation

25 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

26 Autosplenectomy

27 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

28 “Crises” 1.Dactylitis 2.Splenic sequestration 3.Aplastic anemia 4.Acute painful events 5.Acute chest syndrome 6.Neurological events

29 Dactylitis 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

30 Dactylitis

31 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. + O 2 + transfusion

32 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

33 Acute painful events Most frequent symptom after age 2 yrs Vaso-occlusion vs. shunting of blood flow Rx: hydration, O 2 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

34 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)

35 Acute CNS events Overt CVA ~ 5% of children w/ SCD Greatest incidence in 5-10 year olds Silent infarcts in 17% before age 20 Correlates with: –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)

36 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

37 (C.F.) MRA

38 Circle of Willis

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40 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

41 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 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 + 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 10 gm/dl, Hct >30%). 3.Rx seizures if present. 4.Rx increased intracranial pressure if present 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 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  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).

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43 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.

44 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

45 FLUIDS, GENERAL: 1. IV + 1 x maintenance

46 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.

47 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 10 gm/dl, Hct >30%). 3.Rx seizures if present. 4.Rx increased intracranial pressure if present.

48 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 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.

49 DISCHARGE CRITERIA: 1.Clinically and neurologically stable  24 hr. after transfusions. 2.Afebrile  24 hr. with negative cultures for  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).

50 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)

51 Stroke Rx – Adult vs. Children 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

52 New Therapies Hydroxyurea Chronic Transfusion therapy Bone Marrow transplant

53 Hydroxyurea Increases fetal Hb (10 to 25%) Decreases mortality in adults Early information on children suggest safe but efficacy data pending

54 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

55 Bone Marrow Transplant 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

56 Prevention Early diagnosis Vaccinations Penicillin to age 5-6 years or longer Folate Transcranial Doppler (or MRI) Chronic transfusion treatments Parental education

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