FIRSTCONSULT

Sicklecelldisease
Published:May12,2010
CopyrightElsevierBV.Allrightsreserved.

Summary
Description
Sicklecellanemiaisadiseaseoftheerythrocytescausedbyanautosomalrecessivesingle
genedefectintheglobinchainofadulthemoglobin(HbA)thatproducesamutantformof
hemoglobinknownassicklehemoglobin(HbS)
SicklecellanemiaoccursifHbSisinheritedfrombothparents(HbSSgenotype).Other
formsofsicklecelldiseasemayoccurifHbSisinheritedfromoneparentandanother
abnormalhemoglobin,suchashemoglobinC(HbC),orthalassemiaisinheritedfromthe
otherparent(resultinginHbSCorHbSthalassemiagenotype,respectively)
ThetermsicklecellanemiareferstoHbSSdisease,whereasthetermsicklecelldisease
referstoallofthegenotypes
HbSconfersabnormalpropertiestoerythrocytesthecellsbreakaparteasily,andtheir
characteristiccrescentshapecandisruptbloodflow
HbSisassociatedwithvaryingdegreesofanemiaapredispositiontoobstructionofsmall
bloodcapillaries,causingpainful(vasoocclusive)crisesdamagetomajororgansand
increasedvulnerabilitytosevereinfections
Oneofthemostcommonlyinheriteddiseasesworldwide,sicklecelldiseaseispredominant
incertainethnicgroups,particularlyAfricanandAfricanAmericanpopulations
Sicklecelltraitordiseaseoffersaprotectiveeffectagainstmalaria.Inmalariaendemic
regions,thishasledtopositiveselectionofthegeneticmutation
Aholisticapproachtotreatmentisrecommended,withanemphasisonpatienteducation
andguidanceonhomemanagementaswellasonimmediateclinicalneeds
Bonemarrowtransplantationistheonlycurativetreatment
Associatedwithlifelongmorbidityandreducedlifeexpectancy

Synonyms
Sicklecellanemia
HemoglobinSdisease

Urgentaction
Dehydration:fluidreplacementtherapyisrequired,asmostpatientsaremildlydehydrated
duetourineconcentratingdifficulties,whichcanbeexacerbatedbyincreasedsodiumlosses
duringpainfulcrisesandbyconcurrentinfection
Complications:urgentspecialistreferralandemergentmanagementarerequiredforpainful
crisisswollen,painfuljointscentralnervoussystemdeficitsacutesicklechestsyndromeor
pneumoniamesentericsicklingandbowelischemiasplenicorhepaticsequestration
cholecystitisrenalpapillarynecrosisresultingincolicorseverehematuriapriapismand
hyphemaandretinaldetachment
Fever:considerspecialistreferralforfever,asinfectionmayprecipitateanacutepainful
crisis

Keypoints
SicklecellanemiaischaracterizedbyabnormalerythrocytescontainingHbS,whichis
formedastheresultofasinglegenedefectcausingthesubstitutionofvalineforglutamic
acidinpositionsixoftheglobinchainofhemoglobin
Specialistreferralandemergentmanagementarerequiredforpainfulcrisisswollen,painful
jointscentralnervoussystemdeficitsacutesicklechestsyndromeorpneumonia
mesentericsicklingandbowelischemiasplenicorhepaticsequestrationcholecystitisrenal
papillarynecrosisresultingincolicorseverehematuriapriapismandhyphemaandretinal
detachment
Infantsdiagnosedwithsicklecelldiseaseshouldreceivestandardwellchildcare,
immunizations,andprophylacticpenicillin,withmeticulousattentiontocounselingthe
parentorcaregiverregardingtakingtheinfant'stemperatureandbeingobservantforsigns
andsymptomsthatmightindicateanevolvingillness
TheAdvisoryCommitteeonImmunizationPracticesrecommendsthatpneumococcal
polysaccharidevaccinebeadministeredinallimmunocompetentpersonsoverage2whoare
atincreasedriskofillnessanddeathfrompneumococcaldiseaseowingtochronicillness,
includingsicklecelldisease
Manypatientswithsicklecelldiseasecanbeconsideredtobefunctionallyasplenic
beginninginearlychildhood,owingtotherepetitivesicklingandsubsequentinfarctions
withinthespleen

Background
Cardinalfeatures
Sicklecellanemiaisadiseaseoftheerythrocytescausedbyanautosomalrecessivesingle
genedefectintheglobinchainofHbAthatproducesHbS
SicklecellanemiaoccursifHbSisinheritedfrombothparents(HbSSgenotype).Other
formsofsicklecelldiseasemayoccurifHbSisinheritedfromoneparentandanother
abnormalhemoglobin,suchasHbC,orthalassemiaisinheritedfromtheotherparent
(resultinginHbSCorHbSthalassemiagenotype,respectively)
HbSconfersabnormalpropertiestoerythrocytesthecellsbreakaparteasily,andtheir
characteristiccrescentshapecandisruptbloodflow
HbSisassociatedwithvaryingdegreesofanemiaapredispositiontoobstructionofsmall
bloodcapillaries,causingpainfulcrisesdamagetomajororgansandincreased
vulnerabilitytosevereinfections
Themostcommonacuteclinicalpresentationispainfulcrisis
Neonatesareusuallyasymptomatic,andclinicalmanifestationsonlybecomeapparentasthe
levelsoffetalhemoglobin(HbF)declineduringthefirstfewmonthsoflife
Oneofthemostcommonlyinheriteddiseasesworldwide,sicklecelldiseaseispredominant
incertainethnicgroups,particularlyAfricanandAfricanAmericanpopulations
Sicklecelltraitordiseaseoffersaprotectiveeffectagainstmalaria.Inmalariaendemic
regions,thishasledtopositiveselectionofthegeneticmutation
Aholisticapproachtotreatmentisrecommended,withanemphasisonpatienteducation
andguidanceonhomemanagementaswellasonimmediateclinicalneeds
Bonemarrowtransplantationistheonlycurativetreatment

Causes
Commoncauses
Sicklecellanemiaisageneticdisordercausedbyanautosomalrecessivesinglegene
defectintheglobinchainofHbA,whichproducesHbS
HbSisformedbythesubstitutionofvalineforglutamicacidinpositionsixofthe
globinchainofhemoglobin.ErythrocytescontainingHbShaveabnormalproperties
Individualswhoarehomozygousforsicklecellhemoglobin(HbSS)haveaconstellationof
signsandsymptomsthatcharacterizesicklecellanemia

IndividualswhoareheterozygousforHbSarecarriersofthesicklecelltraitanddonot
havepainfulcrises
HbSmayalsobepairedwithotherabnormalhemoglobins,suchasHbCorthalassemia.
Thesepatientshavesicklecelldiseaseandwillhavevaryingclinicalcoursesanddisease
severity

Epidemiology
Incidenceandprevalence
Incidence
4,000to5,000pregnanciesareatriskforsicklecelldiseaseeachyearintheU.S.
6to9millioninfantsareborneachyearwithsicklecelldiseaseinAfrica
Sicklecelldiseaseoccursin1in600AfricanAmericaninfants
Sicklecellanemiaaccountsfor60%to70%ofsicklecelldiseaseintheU.S.

Prevalence
HighestprevalenceamongpeopleofAfrican,AfricanAmerican,Mediterranean
(Italian,Sicilian,Greek),MiddleEastern,EastIndian,Caribbean,andCentralorSouth
Americandescent
8%to10%ofAfricanAmericanneonatesintheU.S.arecarriersofthesicklecelltrait
25%to30%ofneonatesinwesternAfricaarecarriersofthesicklecelltrait

Demographics
Age
Affectedpatientscharacteristicallyareasymptomaticuntilapproximately4to6
monthsofage
Medianageatdeathisapproximately42yearsformenand48yearsforwomen

Race
HighestprevalenceamongpeopleofAfrican,AfricanAmerican,Mediterranean
(Italian,Sicilian,Greek),MiddleEastern,EastIndian,Caribbean,andCentralorSouth
Americandescent
Occursmorecommonlyinpeople(ortheirdescendants)frompartsoftheworldsuch
asSubSaharanAfrica,wheremalariaisorwascommon,butitalsooccursinpeopleof
otherethnicities

Genetics
Sicklecellanemiaisageneticdisordercausedbyanautosomalrecessivesinglegene
defectintheglobinchainofHbA,whichproducesHbS
HbSisformedbythesubstitutionofvalineforglutamicacidinpositionsixofthe
globinchainofhemoglobin.Thevaline,whichisnowabnormallypresentonthe
globinchainofonehemoglobinmolecule,canfitinthehydrophobicpocketofanother
hemoglobinmolecule.Oncethisprocessstarts,thehemoglobinpolymerizeswithinthe
erythrocyte,andthisiswhatcausestheerythrocytetochangeintoitsclassically
describedsickleshape
Hemoglobinopathiesarehighlyprevalentinmalariaendemicareas.Itisthoughtthat
theabnormalhemoglobinprovidesasurvivaladvantage,andthatiswhythemutation
hassurvived
UsuallytheparentsofanindividualwithHbSSareheterozygotesand,therefore,carry
onlyoneHbSalleleandareasymptomatic.However,becauseofthehighrateofHbS
carriersincertainpopulations,itispossiblethataparentmaybehomozygous(HbSS)
oracompoundheterozygote(eg,HbSC)
IfbothparentsareheterozygousfortheHbSmutation(carriers),theriskofhavingan
affectedchildis25%foreachpregnancy
Ifoneparentishomozygous(HbSS)andtheotherparentisheterozygous(HbS),the
riskofhavinganaffectedchildis50%foreachpregnancy
Ifbothparentsarehomozygous(HbSS),alloffspringwillbeaffected
Ifatrisksiblingsofaprobandareunaffected,theriskofachildbeingaheterozygote
(carrier)istwothirds
Eachsiblingforeitheroftheproband'sparentsisat50%orgreaterriskofbeinga
heterozygote.Therefore,athoroughfamilyhistoryshouldbeobtainedtodetermineif
otherhemoglobinopathies(eg,thalassemia)arepresentinfamilymembers
HbSconfersasignificantprotectiveadvantage(>90%insomestudies)againstsevere
andlethalmalaria.Althoughthemalarialparasite,Plasmodiumfalciparum,invades
andmaturesinasimilarfashionasseeninnormalerythrocytes,enhanced
phagocytosisoccursinHbScarriers,causingprematureremovaloftheinfectedcells.
AnimmunologiccomponentdirectedattheP.falciparumerythrocytemembrane
protein1mayfurtherenhancethisprotectiveeffect.Astudyinvestigatingthe
associationbetweenHbSandHbCcarrierstatesandmalariafoundanegative
correlationbetweenHbScarrierstatesandallmajorformsofseveremalaria,butthe
negativecorrelationforHbCcarrierstateswaslimitedtocerebralmalaria

HbSSdiseasepathology:
HbSisformedbythesubstitutionofvalineforglutamicacidinthesecondnucleotide
ofthesixthcodonoftheglobinchainofHbA.Thissinglepointmutationchangesthe
codondeterminingtheaminoacidfromGAGcodingforglutamicacidtoGTGcoding
forvaline
ErythrocytescontainingmutantHbShaveabnormalproperties.Althoughthemutant
hemoglobinsubunitsarenormalintheirabilitytobindoxygen,theyare
considerablylesssolubleindeoxygenatedbloodthannormalhemoglobin.Assuch,and
underconditionsoflowoxygentension,interactionbetweentheabnormalvaline
residueandcomplementaryregionsonadjacentmoleculesresultsintheformationof
intracellular,rodshapedpolymers.Theseabnormalhemoglobinpolymersaggregate
todisruptthecytoskeletonanddistorttheshapeoftheerythrocytes,makingthem
brittleandpoorlydeformable.Thus,unlikenormalerythrocytes,thesickleshaped
cellscannotsqueezethroughthemicrocirculatoryvessels,blockingbloodflowand
resultinginlocalhypoxia
Inadditiontocausingtheobviousshapechange,HbSisalsoinjurioustothe
erythrocytemembrane.Thehemoglobinpolymersdisrupttheattachmentofthe
membranetotheproteincytoskeleton,resultinginexposureoftransmembrane
proteinepitopesandnegativelychargedglycolipidsthatarenormallyfoundinsidethe
cell.Subsequenteffectsofthisexposureincludecellulardehydration,oxidative
damage,increasedadherencetoendothelialcells,andastateofchronicinflammation
andhemolysis

Codes
ICD9code
282.60Sicklecelldisease,unspecified
282.61HbSSdiseasewithoutcrisis
282.62HbSSdiseasewithcrisis
282.63Sicklecelldisease/HbCdiseasewithoutcrisis
282.68Othersicklecelldiseasewithoutcrisis
282.69Othersicklecelldiseasewithcrisis
282.41Sicklecellthalassemiawithoutcrisis
282.42Sicklecellthalassemiawithcrisis

Diagnosis
Clinicalpresentation
Infantsareusuallyasymptomaticuntil4monthsofage,whenhemolyticanemiamayfirst
becomeapparent.Theymaypresentwithsymptomsofmoderateanemiaby6to12months
ofageorwithmoreseriouscrisisandpain.Painfulswellingofthehandsandfeet,knownas
handfootsyndromeordactylitis,isoftenoneofthefirstpresentationsofsicklecelldisease
Clinicalfeaturesvarygreatlyfrompatienttopatientandmaybedueeithertotheacutevaso
occlusiveconsequencesofsicklecellsorthechronichemolysisandresultantanemia.Some
individualsmayremaintotallyasymptomaticintolatechildhood,orthediagnosismaybe
arrivedatonlyincidentally

Symptoms
Chronic:
Excessivetirednessandfatigability
Pain,particularlyinthebackandhipsbutcanoccuranywhere
Breathlessnessonexertion
Decreasedexercisetolerance
Growthanddevelopmentaldelay
Jaundice
Visualdisturbances,especiallynewonsetoffloaters
Acute:
Acutechestsyndrome:chestpainandfever
Painfulcrises:persistentpain,particularlyintheskeleton,chest,and/orabdomenbut
canbealmostanywhere
Infection:malaise,coughandchestpain,diarrheaand/orvomiting
Dactylitis:swollenandpainfulhandsandfeet(by2yearsofage,50%ofJamaican
childrenand25%ofAmericanchildrenwithsicklecellanemiahaveexperiencedatleast
oneepisode)
Splenicsequestration:abdominaldiscomfortduetosplenomegalyandtrappingof
erythrocytesinthespleen

Stroke(affects10%ofpatients6%17%ofchildrenandyoungadults):suddenneurologic

deficits,includingmotordeficitsdifficultywithlanguage,writing,and/orreading
seizuressensorydeficitsalteredconsciousness
Cholecystitis:hemolysisleadstopigmentstonesinthegallbladderpresentswithjaundice

andabdominalpain
Lossofvision:canbeprecededbyfloaters
Priapism

Signs
Chronic:
Notableimpairmentofgrowthanddevelopment
Hepatomegalyand/orsplenomegaly
Pallor
Jaundice
Cardiomegaly,ahyperdynamicprecordium,andagradeIIIIIsystolicejectionmurmur
Ocularabnormalitiesproliferativeretinopathy,retinalneovascularization('seafan'),
retinalhemorrhage
Legulcers,typicallyappearingasashallowdepressionwithasmoothandslightly
elevatedmarginandasurroundingareaofedema
Bonydeformitiesofdifferenttypes
Paleurineduetoimpairedurineconcentratingability
Acute:
Anemia:pallor
Acutechestsyndrome:sicklingoferythrocyteswithinthepulmonaryvasculature,which
canbeclinicallyindistinguishablefrompneumoniaandcancausechestpain,fever,
dyspnea,tachypnea,andhypoxemia
Infection:oraltemperatureabove38.5C(101.3F),cough,waterystools,tender
abdomen
Dactylitis:swollendorsaofhandsandfeet,whichcanbeapresentingsymptomininfants
andchildren

Boneinfarctionandavascularnecrosis(particularlyofthefemoralhead):fromvaso
occlusivecrisis,causinglimitedrangeofmotionoftheaffectedjoint
Priapism:sustainedandpainfulpenileerection(occursin50%ofallmalepatients)
Aplasticcrisis:transientcessationoferythrocyteproduction,oftentriggeredbyaviral
infectionandcharacterizedbypallor,tachypnea,andtachycardiawithoutsplenomegaly
Splenicsequestration:splenomegaly,pallor,tachycardia,andpossibleshockfrom
trappingoferythrocytesinthespleen
Stroke:mentalstatuschanges,neurologicdeficits

Associateddisorders
Nearlyeveryorgansystemmaybeaffected.Examplesofassociateddisordersinclude:
Ocular:retinalhemorrhage,retinopathy,and/orblindness
Cardiac:congestiveheartfailure
Pulmonary:pulmonaryhypertension,pulmonaryembolism
Hepatic:hepaticinfarctionorhepatitisresultingfromtransfusioncirrhosisfrom
transfusionrelatedironoverloadsickleintrahepaticcholestasishepaticsequestration
Gallbladder:increasedincidenceofpigmentgallstones
Urinary:hyposthenuria,hematuria,renalpapillarynecrosis,chronickidneydisease,gout
Genital:decreasedfertility,impotence
Neurologic:stroke
Skeletal:avascularnecrosis,skullbossing,gnathopathy,andotherbonydeformities
osteomyelitis

Differentialdiagnosis
Thedifferentialdiagnosisofsicklecellanemiaisdependentonthesymptomsofthepatientat
presentation.

Disordersinvolvingthejoints

Sicklecelldiseasecanpresentwithswollenjointsinachild.Swellingofthejointsasa
manifestationofavasoocclusivecrisisislesscommoninadults.Dactylitispresentsatanearly
ageandoccursonlyinthehandsandfeet,whichcanhelpdifferentiateitfromother

rheumatologicdiseases.Jointswellinginanadultrequiresmoreextensiveevaluation.Adults
usuallyknowwhattheirtypicalpainfeelslike,andfurtherworkupiswarrantedwhenpainis
atypical.

Features
Gout:canbeseeninpatientswithsicklecelldiseasewhohaveassociatedrenaldisease

workupshouldincludejointaspirationtolookformonosodiumuratecrystals
Septicarthritis:featuresincludepainfulswellingoftheaffectedjointandfeverfurther

evaluationwithabonescanormagneticresonanceimaging(MRI)maybeindicated
Connectivetissuediseases:oftenpresentwithpainfuljointsserologicworkupshould
bedonetoexcludethesediseasesinpatientswithatypicalpainorotherassociated
findings(eg,rash)
Avascularnecrosis:presentswithpaintypicallyinthehiporshoulderandcanbe
differentiatedfromavasoocclusivecrisisbyitschronicityifsuspected,MRIofthe
affectedjointcanconfirmthediagnosis

Acuteabdominaldisorders

Abdominalpaincrisesowingtosmallinfarctoftheabdominalvisceramustbedifferentiated
fromotheracuteabdominaldisorders.Differentialdiagnosesforrightupperquadrant
abdominalpaininapatientwithsicklecelldiseaseareextensiveandincludeacutecholelithiasis,
hepaticcrises,hepaticsequestration,sicklecellintrahepaticcholestasis,biloma,hepaticvein
thrombosis,pancreatitis,pulmonaryinfarct,renalveinthrombosis,andfocalnodular
hyperplasiaoftheliverinchildren.Fullworkup,includingcompletebloodcount(CBC),
comprehensivebloodpanel,amylase,lipase,andurinalysis,shouldbedoneinthesepatients.
Radiologicimaging,suchasultrasoundorcomputedtomography(CT)scanoftheabdomen,
maybeusefulinsomecasestodistinguishvasoocclusivecrisesfromacuteabdominal
disorders.

Features
Severeabdominalpain
Signsofperitonealirritation
Absenceofbowelsounds

Osteomyelitis

Painfulboneepisodesinpatientswithsicklecellanemiaareclinicallyindistinguishablefrom
thoseexperiencedbypatientswithosteomyelitismagneticresonancebonescansusing
technetiumandgalliumstainingcanbehelpfulinconfirmingadiagnosis.

Features
Multifocalsymptomsareuncommon
PositivebloodcultureresultsforSalmonellaspecies,Staphylococcusaureus,and/or
Streptococcuspneumoniaefavorthediagnosisofosteomyelitis
Presenceoffeverismoreconsistentwithosteomyelitis,althoughfevermaybepresent
ifavasoocclusivecrisisisbroughtonbyinfection,makingitdifficulttodistinguish
betweenthetwo
Painisusuallyisolatedtoonespotandoftendoesnotresolvewithinthesameamount
oftimeasatypicalvasoocclusivecrisis

Otherseverelypainfulmedicalconditions

Themostpredominantclinicalsymptomofsicklecelldiseaseisrecurrentepisodesofpain
involvingthechest,abdomen,andskeleton.Thepaincanbesimilartothatexperiencedin
otherconditions,suchaspulmonaryembolismorrenalcolic.Acarefulhistoryandphysical
examinationcanoftenhelpdistinguishbetweenavasoocclusivecrisisandamoreserious
complication.

Congenitalsyphilis

Congenitalsyphilisisacquiredinuterobyoffspringofwomenwithuntreatedsyphilisduring
pregnancy.Inearlyinfancy,childrenwithcongenitalsyphilismaypresentwithdactylitisor
osteitisthatmimicssicklecelldactylitis.Ifcongenitalsyphilisissuspected,maternalsyphilis
testingcanaidindiagnosis.

Features
Usuallypresentswithrhinitisfollowedbyadiffuse,desquamatingmaculopapular
rash,whichmaybecomevesicular
Radialskinlesionsaroundthemoutharecommon
Boneinvolvementiscommonradiographicabnormalitiesmayincludemultipleareas
ofosteitisosteochondritisandperiostitisofthelongbonesand,rarely,theskull
Osteochondritisispainfulandoftenresultsinirritabilityandrefusaltomovethe
involvedextremity
Splenomegaly,anemia,thrombocytopenia,andjaundicemayresultfromhepatic
involvement
Immunecomplexglomerulonephritismayresultfromrenalinvolvement
Mostcasesofuntreatedcongenitalsyphilisininfantswhosurvivefor6to12months

progresstolatentsyphilis,andneurosyphilisdevelopslaterinlifesomeoftheskeletal
andsofttissuemanifestationsofcongenitalsyphilisarepermanent

Trauma

Painfulcrisesofsicklecelldiseasemayresultinpainintheskeleton,chest,orabdomen,which
maymimictrauma.Obtainingahistoryisusuallyveryhelpful,althoughahistoryoftraumais
notalwaysobviousininfants.Intheabsenceofahistory,traumaisdifficulttodistinguishfrom
infarctioninpatientswithsicklecelldisease,inwhomperipheralbloodsmearfrequentlyshows
sicklecellforms.Iftraumaissuspectedinachildwhocannotcommunicate,imagingofthe
affectedarea,alongwithcloseobservation,ishelpful.

Features
Painrelatedtothesiteoftrauma
Signsofinjuryortrauma
Historyconsistentwithsymptoms

Workup
Diagnosticdecision
IntheU.S.,universalneonatalscreeningispracticedinmoststates,asscreeningisthe
onlywaytoensurethatallinfantswithsicklecelldiseaseareidentified.Screeninginfants
onlyfromspecificracialorethnicgroupsisnotreliable
Bloodsamplesshouldbecollectedbeforetransfusionusingthesamemethodasforother
neonatalscreeningtestsbyheelstickontofilterpaper.Neonatalbloodsamplesareoften
collectedandsentforanalysisasagrouptofacilitatetesting
Determinationofaninfant'shemoglobintypecanbedonebymultiplelaboratory
methods,butwhentheresultisfoundtobeabnormal,thelaboratorymusthaveasystem
inplaceforrapidcommunicationofresultstothepatient'shealthcareprovider
Itisthephysician'sresponsibilitytoensurethatthediagnosisisconfirmedby
hemoglobinelectrophoresis,alongwithaCBC,reticulocytecount,andbloodsmear
Appropriatereferraltoaspecialtysicklecellclinicforeducation,geneticcounseling,and
routinefollowupcareisessentialandshouldoccurassoonasthediagnosisisestablished

Guidelines
TheNationalHeart,Lung,andBloodInstitute(http://www.nhlbi.nih.gov/)hasproducedthefollowing:
TheManagementofSickleCellDisease
(http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf).NIHPublicationNo.022117.

Bethesda,MD:NationalHeart,Lung,andBloodInstitute2002
TheBritishSocietyforHaematology(http://www.bsh.org.uk/)hasproducedthefollowing:
ReesDC,OlujohungbeAD,ParkerNE,StephensAD,TelferP,WrightJBritish
CommitteeforStandardsinHaematologyGeneralHaematologyTaskForcebythe
SickleCellWorkingParty.Guidelinesforthemanagementoftheacutepainfulcrisisinsickle
celldisease(http://www.bcshguidelines.com/pdf/sicklecelldisease_0503.pdf).BrJHaematol.
2003120:74452
TheAmericanAcademyofFamilyPhysicians(http://www.aafp.org)haspublishedthefollowing:
WethersDL.Sicklecelldiseaseinchildhood.PartI.Laboratorydiagnosis,pathophysiologyand
healthmaintenance(http://www.aafp.org/afp/20000901/1013.html).AmFamPhysician.

200062:101320
WethersDL.Sicklecelldiseaseinchildhood:partII.Diagnosisandtreatmentofmajor
complicationsandrecentadvancesintreatment(http://www.aafp.org/afp/20000915/1309.html).

AmFamPhysician.200062:130914
YaleSH,NagibN,GuthrieT.Approachtothevasoocclusivecrisisinadultswithsicklecell
disease(http://www.aafp.org/afp/20000301/1349.html).AmFamPhysician.200061:1349
56

Don'tmiss!
Acuteinfections,whichmaybethecauseofthecrisisandcanbetreatedwithantibiotic
therapy
Acuteabdominalproblems,whichmaymimicacrisisorbethecauseofacrisis

Questionstoask
Presentingcondition
Forparentsorcaregiversofaninfant:
Howlonghastheinfantbeenunwell?Infantswithsicklecelldiseaseareusually
asymptomaticuntil4monthsofageandthenoftenhavesymptomsofmoderate
anemiaormoreseriouscrisisandpainby6to12monthsofage
Didtheinfanthavejaundiceatbirth?Jaundicemaybeachronicsymptomof
sicklecellanemia
Hastheinfantingestedanythingunusual?Drugsareacommoncauseof
hemolysisininfants

Hastheinfantbeengrowingwell?Infantswithsicklecellanemiamaypresent
withfailuretothriveandsevereanemiaandjaundiceatapproximately6monthsofage
Hastheinfanthadafever?Childrenwithsicklecellanemiaaresusceptibleto
acuteinfectionduetodamagetothespleen
Hastheinfant'sabdomenbeentenderorappearedenlarged?Childrenwith
sicklecellanemiamayhavehepatomegalyand/orsplenomegaly
Forolderchildrenandadults:
Haveyoualwaysbeenpale?Haveyoubeenanemic?Haveyoueverhad
jaundice?Pallor,intermittenticterus,andsplenomegalyarecommon
Doyoueverhavepaininyourstomachorjoints?Patientsmayexperience
persistentpaininthejoints,skeleton,chest,and/orabdomen
Haveyoueverhadswellingofyourhandsorfeet?Dactylitisiscommonin
childrenwithsicklecellanemia(by2yearsofage,50%ofJamaicanchildrenand25%
ofAmericanchildrenwithsicklecellanemiahaveexperiencedatleastoneepisode)
Haveyoueverhadasustained,painfulpenileerection?Priapismoccursin
50%ofallmalepatients
Haveyoueverhadgallstones?Gallstonesareacommoncomplicationofsickle
cellanemiaduetoincreasedlevelsofbilirubinintheblood
Haveyoueverhadlegulcers?Legulcersareacommoncomplicationofsicklecell
anemia,usuallystartingassmall,raised,crustedsoresonthelowerthirdoftheleg.
Theyoccurmoreofteninmalepatientsthaninfemalepatientsandusuallyoccurin
patientsoverage10.Thecauseoflegulcersinthesepatientsisunclear
Haveyouhadafever?Childrenwithsicklecellanemiaaresusceptibletoacute
infectionduetodamagetothespleen
Forpatientspresentingwithacutecrisis:
Areyouregisteredwithaspecialistclinic?Allpatientswithsicklecelldisease
shouldberegisteredwithandmonitoredbyaspecializedsicklecellclinic.Sicklecell
clinicscanprovideimportantinformationondiseaseseverity,pastclinical
manifestations,andcurrentandprevioustreatmentregimen
Canyoudescribetheseverity,location,anddurationofpain,ifany?Acute
painfulepisodesrepresentthemostfrequentandprominentmanifestationofsickle
celldisease,andfrequentandrigorouspainassessmentisrequiredtoensureadequate
painmanagement

Familyhistory
Haseitherparentbeendiagnosedwithsicklecellanemiaoranyother
hemoglobinopathy?Sicklecelldiseaseisahereditaryconditioninvolvinga
recessivesinglegenedefectofHbA
Havebothparentsbeenscreenedforsicklecelldiseaseorthalassemia,or
iseitherparentawareofhavinganotherabnormaltypeofhemoglobin(eg
,HbC)?Individualsheterozygousforanabnormalhemoglobingeneare
asymptomaticcarrierswhocanpassthetraitontotheiroffspring

Examination
Observethepatientforpallorandjaundice:indicativeofhemolysis
Recordpresenceorabsenceofapalpablespleen,andestimateandrecord
sizeofspleen:indicativeofsplenicsequestration
Recordsizeofliver:indicativeofhepaticsequestration
Notepresenceorabsenceofacardiacmurmur:indicativeofcardiac
abnormalitiesowingtochronicanemiaorasuddenchangeinhemoglobinlevel
Takemeasurementsandnotedevelopmentalstage:recordandchartthepatient's
height,weight,andheadcircumferencerecordstageofsexualdevelopment(Tanner
stage)
Observegait:noteandrecordgait
Documentpulseoximetryreading

Summaryoftests
Prenataldiagnosis:
Atriskcoupleswhoaretryingtoconceiveandwomenwhoarepregnantshouldbe
offeredgeneticcounselingtodiscussavailablecarrierdetectionmethodsandtheoption
ofsubsequentprenataltesting,ifappropriate
Eachparentshouldhavefullanalysisofbothglobinallelesbeforeprenataltestingis
doneintheeventthatoneparentmaybeacarrierofanonHbSmutationthat
predisposestoadifferenthemoglobinopathy(eg,HbSthalassemiaorHbSC)
Methodssuchasisoelectricfocusinganddeoxyribonucleicacid(DNA)basedassaysmay
beusedinconjunctionwithhighperformanceliquidchromatography(HPLC)todetect
quantitativehemoglobinabnormalities,suchasthalassemias
DNAanalysis(ZDCDCD36_4E_145)isusedforprenataldiagnosissamplesfortestingare

usuallyobtainedbychorionicvillussamplingat10to12weeksofgestationor
amniocentesisat14to18weeksofgestation
Ageneticcounselorshouldalwaysbeconsultedtoadviseandinformtheparents
Testingofotherfamilymembersshouldalsobediscussedonceadiagnosishasbeen
established
Techniquesforpreimplantationdiagnostictestingmaybeavailableforfamiliesinwhich
thediseasecausingmutationshavebeenidentified
Neonatalscreening:
Routineneonatalscreeningforsicklecellanemiaisdoneinall50statesintheU.S.,the
DistrictofColumbia,PuertoRico,andtheVirginIslands,allowingearlydiagnosisand
intervention(preventionofbacterialinfectioninparticular)
Mostscreeningprogramsfavoruniversaltestingratherthanselectivetestingofatrisk
infants.Themajorityofnewcasesarediagnosedatbirth
Hemoglobinstudies(130224):bloodsamplesareusuallyobtainedbyheelstick,anda

hemoglobinevaluationisdone,usuallywithin3daysofbirth.Confirmatorytesting
shouldbedonewithin2months
Hemoglobinsolubilitytestingcanbedoneatafollowupappointmentbutisnot
recommendedininfantsunder6monthsofagebecausethehighproportionofHbFin
relationtoHbSinaneonate'sbloodmayaffecttheresults
AbnormalresultscanbeconfirmedbyDNAanalysis
Diagnosisinolderchildrenandadults:
CBCandreticulocytecount(ZDCE2683_185_26):maybeusedtoevaluatethenumberand

qualityoferythrocytes,hemoglobincontent,andleukocytecount
Peripheralbloodsmear(59398):microscopicanalysisofabloodspecimengivesvital

informationonerythrocytemorphology
Hemoglobinsolubilitytesting(ZDCE1AE6_313_373):maybeusedfirsttoscreenforHbS

however,itcannotdistinguishbetweensicklecelltrait(heterozygosity)andsicklecell
disease(homozygosity)
Hemoglobinstudies(130224):usedtodefinethespecifichemoglobinopathy

electrophoresis,isoelectricfocusing,orHPLCareusedtomeasurethetypeandrelative
amountsofhemoglobinpresentintheerythrocytes.Indirectly,thisallowsthedistinction
betweenheterozygosityandhomozygositytobemade

DNAanalysis(ZDCDCD36_4E_145):maybeusedtoconfirmthepresenceofsicklecell

diseaseorsicklecelltrait.Familystudiesmayalsobedonetoidentifysicklecelltraitin
otherfamilymembers
Ironstudies(ZDCE26DD_201_114):maybeindicatedinpatientspresentingwithanemiato

helpdeterminewhetherirondeficiencyisthecause
Furtherevaluation:
Baselinehemoglobinlevel,hematocrit,reticulocytecount,leukocytecount,hepaticand
renalfunction,andironlevelsshouldberecordedandcheckedatleastonceayear
Urinalysis(1100141):shouldbedoneatleastonceayearbecauseearlysignsofrenal

diseasecanbeinsidious.Findingsofmicroscopichematuriaorpersistentproteinuria
shouldbeinvestigated.Urinalysisshouldalwaysbedoneinpatientspresentingwith
acuteabdominalpaintoruleoutacuteinfectionorrenalcalculusaswellasrenal
thrombosis
Chemistrypanel(1100147):electrolyte,bloodureanitrogen(BUN),andcreatininelevels

shouldbeobtainedtolookformanifestationsofimpairmentsinrenalacidificationand
potassiumsecretionaswellasrenalinsufficiencyduetosicklecellnephropathy
Bacterialcultures(130266):shouldbeobtainedasneededtoexcludeinfectionintoxic

and/orfebrilepatients
Chestradiograph(ZDD488F1_270_73):obtainedinpatientswithacutechestsyndrometo

excludeotherdisordersshouldbeconsideredinpatientswithrespiratorysymptoms,
fever,orchestpain
Skeletalradiographs(59422):maybehelpfulinselectedpatientswithapresumedpainful

crisisnotrespondingtostandardtherapyorinpatientswithpainthatisatypicalforsickle
celldiseasecanbeusedtolookforavascularnecrosisorosteomyelitis
TranscranialDopplerultrasound(1100153):intracranialvessels,especiallythecarotid

arteries,areevaluatedbyDopplerflowstudiestohelpassesstheriskofstroke
Echocardiography(1100175):recommendedtoscreenpatientsforpulmonaryhypertension

canbeusedtoevaluatecardiacfunctionaswellasgiveanestimateofpulmonary
pressures
MRI(1100159)andbonescans(1100195)usingtechnetiumandgallium:canhelp

differentiateboneinfarctionsfromosteomyelitissecondarytoinfection
Abdominalultrasound(1100168):canbeusedtodocumentspleensizeandthepresenceof

biliarystones

After10yearsofage,carefulretinalexamination(59437)shouldbedoneannuallybyan
ophthalmologisttoassessforretinaldisease

Orderoftests
CBCandreticulocytecount(ZDCE2683_185_26)
Peripheralbloodsmear(59398)
Hemoglobinsolubilitytesting(ZDCE1AE6_313_373)
Hemoglobinstudies(130224)
DNAanalysis(ZDCDCD36_4E_145)
Ironstudies(ZDCE26DD_201_114)
Urinalysis(1100141)
Chemistrypanel(1100147)
Chestradiograph(ZDD488F1_270_73)
Skeletalradiographs(59422)
TranscranialDopplerultrasound(1100153)
Echocardiography(1100175)
Retinalexamination(59437)
Bacterialcultures(130266)
MRI(1100159)
Bonescan(1100195)
Abdominalultrasound(1100168)

Tests
Bodyfluids

CBCandreticulocytecount

Description
Venousbloodsample
Laboratoryanalysisprovideserythrocytecount,hemoglobin/hematocrit,
erythrocyteindexes,leukocytecount,plateletcount,andreticulocytecount

Usefulinestablishingbaselinevaluesforongoingevaluation

Advantages/disadvantages
Advantages:
Simple,rapid,andwidelyavailable
Confirmsanemia
Documentshyperproliferativeanemiawithelevatedreticulocytecount
Capillarytubeofbloodcanbeused
Disadvantage:
Notdiagnostic

Normal
Resultsshouldbewithintheagespecificlaboratoryreferenceranges.
Hemoglobin:13.1to16.8g/dL(131168g/L)inmen11.2to15.0g/dL(112150
g/L)inwomen
Erythrocytes:4.3to5.7106/mm3(4.35.71012/L)inmen3.7to5.1
106/mm3(3.75.11012/L)inwomen
Leukocytes:3,800to11,000/mm3(3.811.0109/L)inmen3,600to
11,000/mm3(3.611.0109/L)inwomen
Neutrophils:44.6%to76.5%
Platelets:156to352103/mm3(156352109/L)inmen163to380
103/mm3(163380109/L)inwomen
Reticulocytes:0.4%to2.4%

Abnormal
Resultsoutsideoftheagespecificlaboratoryreferenceranges.
Hemoglobin<11g/dL(<110g/L)
Elevatedtotalleukocytecountwithpredominanceofneutrophils
Elevatedplateletcount

Reticulocytecountsrangingfrom>2%to30%

Causeofabnormalresult
Anemiaduetosicklehemoglobinopathy(homozygote,heterozygote,orcompound
heterozygotewithanotherabnormalglobinmutation).

Medications,disorders,andotherfactorsthatmayalterresults
MultipleotherconditionsandetiologiesofanemiacanaffecttheCBC.

Peripheralbloodsmear

Description
Bloodspecimenisobtained,andathinlayerofbloodisstainedandexamined
underamicroscope
Anestimateofthenumberandevaluationofthetypeofleukocytes,erythrocytes,
andplateletsisobtainedtoassessifthecellsarenormalandmature
Allowsvisualizationofsickleshapedcells,HowellJollybodies,nucleated
erythrocytes,andcellfragments

Advantages/disadvantages
Advantages:
Simpleandinexpensive
Usefulinrulingoutadditionalcausesofanemia
Disadvantages:
Subjectiverequiresknowledgeoferythrocytemorphology,expertinterpretation
Cannotbeusedtodetermineifvasoocclusivecrisisisoccurring

Normal
Normaldifferential
Normalappearanceofcells

Abnormal
Presenceofnucleatederythrocytes,sickleshapedcells,andHowellJollybodies
Elevatedtotalleukocytecountwithpredominanceofneutrophils
Elevatedplateletcount

Causeofabnormalresult
PresenceofHbS.

Hemoglobinsolubilitytesting

Description
VenousbloodsampleobtainedtodetectthepresenceofHbS
Achemicalisaddedtothesampletoreducetheamountofoxygenthebloodcan
carry
ReductioninoxygenwillcauseSrelatedpolymerstoformandtheaffected
erythrocytestosickle

Advantages/disadvantages
Advantages:
Simpleandinexpensive
DetectsHbS
Usefulforscreening
Excludessicklecelldiseaseinpatientsolderthan6monthswithoutsymptomsor
signsofsevereanemiaorveryhighHbFlevels
Disadvantages:
Shouldnotbedoneininfantsuntiltheyare6monthsoldorolderduetothelow
amountsofHbSproduceduntilseveralmonthsafterbirth
Cannotdistinguishbetweensicklecelldiseaseandsicklecelltrait
Cannotruleoutorconfirmthepresenceofspecifictypesofabnormal
hemoglobin

Normal
Normalerythrocytes
AbsenceofHbS

Abnormal
10%ormoreHbS.

Causeofabnormalresult

Sicklecelldiseaseortrait.

Hemoglobinstudies

Description
Venousbloodsample
Severalmethodsareavailabletoevaluatethetypeandrelativeamountof
hemoglobinpresent:electrophoresisusingcelluloseacetateoracidcitrateagar,
isoelectricfocusing,orhemoglobinfractionationusingHPLC
Withhemoglobinelectrophoresis,thesampleissubjectedtoanelectromagnetic
fielddifferenttypesofhemoglobinwillmigrateinpatterns,formingunique
bandsthatenableconfirmationofthediagnosis
Allneonatalscreeningisdoneusingthemoresensitivehemoglobinisoelectric
focusingorHPLCfractionation
Inolderchildrenandadults,celluloseacetateelectrophoresisatanalkalinepHis
mostcommonlyusedtodeterminethehemoglobinsubtypeanalternative
methodcanbeusedtoconfirmthediagnosis

Advantages/disadvantages
Advantages:
Confirmsthediagnosisofsicklecellanemia
Canexcludeotherhemoglobinopathies
IdentifiesheterozygousHbS,sicklecelltraitiftheotherhemoglobinis
predominantlyHbA,andotherformsofsicklecelldisease(HbSC,HbS
thalassemia)
CanalsobeusedtodeterminethepercentageofHbSinabloodsample.Thisis
particularlyhelpfulinguidingandmonitoringtreatment(eg,indetermining
howeffectivesimpleorexchangetransfusionhasbeenindecreasingthelevelof
sickledcells)
Disadvantages:
DiagnosisinearlyinfancyismoredifficultbecauseofthehighamountofHbF
Unreliableininfantsorpatientswhohavereceivedabloodtransfusionrepeat
testingorDNAtestingisrequired

Normal

PresenceofonlynormalHbF,Hb2,andHbA(proportiondependsonpatientage).

Abnormal
Inneonateswithsicklecelldisease,HbFwillpredominate,butsomeHbSwillbe
present
Inolderinfants,theamountofHbSwillincreaseasHbFdecreases
By2yearsofage,theamountofHbSandHbFstabilizes
OlderpatientswithsicklecellanemiawillhavenoHbA
Patientswhoareheterozygousfortwodifferenthemoglobinvariants(eg,HbSC)
willusuallyproducevaryingamountsofbothtypes
Adultpatientswithsicklecelltraitwillcontinuetoproduceamajorityofnormal
HbA
DistinguishingHbSthalassemiafromsicklecelltraitcanbedifficult.Theusual
findingisthatpatientswithsicklecelltraithave60%HbAand40%HbS,
whereaspatientswithHbSthalassemiahave60%HbSand40%HbA
Resultsforolderchildren:
Sicklecellanemia:75%to95%HbS,2%to20%HbF,andnotablyabsentHbA
Sicklecelltrait:20%to40%HbS,<2%HbF,and50%to60%HbA

Causeofabnormalresult
Sicklecelldiseaseorsicklecelltrait
Identificationofhomozygosity(HbSS)confirmsthediagnosisofsicklecell
anemiaandexcludesotherhemoglobinopathies
Identificationofheterozygositycanindicatesicklecelltraitiftheother
hemoglobinispredominantlyHbAorcanconfirmthediagnosisofotherformsof
sicklecelldisease(HbSC,HbSthalassemia)

DNAanalysis

Description
DirectmutationanalysisfortheE6VmutationassociatedwithHbSandother
mutationsassociatedwithotherspecifichemoglobinvariantsisavailable
FullDNAsequenceanalysisoftheglobingene(HBB)maybeusedifdirect

mutationanalysisisuninformative
Assessesthegenesthatproducehemoglobincomponentsforalterationsand
mutations
UsedtodeterminewhetherapatienthasonecopyoftheHbSmutation,two
copies,orcopiesofdifferenthemoglobinvariants
Maybeorderedforprenataltestingortoconfirmadiagnosis
Familystudiescanbedonetoidentifysicklecelltraitorsicklecelldiseasein
otherfamilymembers

Advantages/disadvantages
Advantages:
Providesthemostaccuratediagnosis
Confirmsthediagnosisofsicklecellanemia,sicklecelltrait,andotherHBBgene
variants
Disadvantage:
Relativelyexpensive

Abnormal
PresenceofmutationsoralterationsintheHBBgene.

Causeofabnormalresult
ReplacementofbothglobinsubunitswithHbSconfirmsthediagnosisofsickle
cellanemia(HbSS)
ThepresenceofonenormalglobinsubunitandoneHbSconfirmsthe
diagnosisofsicklecelltrait
Othermutationsthatcausesicklecelldiseasemaybeidentified,suchasthose
causingthalassemia,methemoglobinemia(hemoglobinM),andtheproduction
ofhemoglobinvariantsHbCandHbE

Ironstudies

Description
Venousbloodsample
Serumferritin,transferrin,andironbindingcapacityaremeasured

Advantages/disadvantages
Advantages:
Easilydoneinconjunctionwithotherstandardbloodtests
Helpsdistinguishhemolyticanemiafromirondeficiencyanemia

Normal
Serumferritin:18to300ng/mL(18300g/L)
Serumtransferrin:170to370mg/dL(1.73.7g/L)
Serumironbindingcapacity:250to460g/dL(4582mol/L)

Abnormal
Serumironandtransferrinlevelsandserumironbindingcapacityareeithertoohigh
ortoolow.

Causeofabnormalresult
Serumtransferrinlevelsandserumironbindingcapacityareelevatedandserum
ferritinlevelsaredecreasedinpatientswithirondeficiency
Serumtransferrinlevelsandserumironbindingcapacitycanbedecreasedin
patientswithhemolyticanemia

Urinalysis

Description
Usedtolookformicroalbuminuriaorfrankproteinuria,hematuria,and/or
urinarytractinfectioninpatientswithsicklecelldisease
Urinespecificgravitycanalsobehelpfulinevaluatingpatientsforisosthenuria

Advantages/disadvantages
Advantage:
Importanttooltodetectearlykidneydiseaseandotherrenalcomplicationsof
sicklecelldisease
Disadvantage:
Cannotquantifyproteinuria

Abnormal

Isosthenuria,especiallyafterfluidrestriction
Presenceofproteininurine
Presenceoferythrocytes(>27cells/L)inurine,suggestinghematuria
Presenceofleukocytes(>27cells/L)inurinewithpositiveleukocyteesterase
and/ornitritedipsticktestresult,suggestingurinarytractinfection

Causeofabnormalresult
Proteinuria:kidneydamageduetosicklecelldisease
Erythrocytesintheurine,suggestinghematuria:papillarynecrosis
Leukocytesintheurinewithapositiveleukocyteesteraseand/ornitritedipstick
testresult:urinarytractinfection

Chemistrypanel

Description
Venousbloodsample.

Advantages/disadvantages
Advantages:
Simple,readilyavailable,andinexpensive
Assesseswhetherrenalfunctionisimpaired

Normal
Sodium:136to142mEq/L(136142mmol/L)
Potassium:3.5to5.0mEq/L(3.55.0mmol/L)
Chloride:96to106mEq/L(96106mmol/L)
Bicarbonate:21to28mEq/L(2128mmol/L)
BUN:8to23mg/dL(3.08.2mmol/L)
Creatinine:0.6to1.2mg/dL(50110mol/L)

Abnormal
Sodium:<136mEq/L(136mmol/L)or>142mEq/L(142mmol/L)
Potassium:<3.5mEq/L(3.5mmol/L)or>5.0mEq/L(5.0mmol/L)

Chloride:<96mEq/L(96mmol/L)or>106mEq/L(106mmol/L)
Bicarbonate:<21mEq/L(21mmol/L)or>28mEq/L(28mmol/L)
BUN:<8mg/dL(3.0mmol/L)or>23mg/dL(8.2mmol/L)
Creatinine:<0.6mg/dL(50mol/L)or>1.2mg/dL(110mol/L)

Causeofabnormalresult
Impairmentsinrenalacidificationandpotassiumsecretion
Renalinsufficiencyduetosicklecellnephropathy

Bacterialcultures

Description
Sterilecollectionofrelevantspecimens(eg,blood,urine,and/orpus)in
appropriateculturebottlesforlaboratoryanalysis
Bacterialculturesshouldbeobtainedinpatientswithfeverand/orthosewho
appeartoxic
Urineandpuscultureresultsareusuallyavailablewithin24to48hours,and
bloodcultureresultsareavailablewithin48to72hours

Advantages/disadvantages
Advantages:
Allowidentificationofassociatedbacterialinfection
Identifybacterialpathogen,allowingsusceptibilitytestingtoguideselectionof
appropriateantibiotics

Normal
Nobacterialpathogencultured.

Abnormal
Bacterialpathogencultured.

Causeofabnormalresult
Associatedbacterialinfection.

Medications,disorders,andotherfactorsthatmayalterresults
Previousantibiotictherapy(couldcreateafalsenegativeresult)

Inadequatequantityofbloodintheculturebottle(couldleadtoafalsenegative
bloodcultureresult)
Failuretousesterileproceduretoobtaintheculturespecimen(couldresultin
contaminationbyskin,mouth,orbowelfloraandleadtoanunreliableresult)

Imaging

Chestradiograph

Description
Shouldbeobtainedifthepatienthasrespiratorysymptomsorchestpain
Presenceofanewinfiltrateaccompaniedbyfeverandchestpainisdiagnosticof
acutechestsyndrome

Advantages/disadvantages
Advantage:
Canaidinthediagnosisofacutechestsyndromeorpneumonia
Disadvantage:
Findingsmaybenormalinitially

Abnormal
Presenceofpulmonaryinfiltrate(s),whichmayextendrapidly,involvingoneormore
lobesaswellasthepleura.

Causeofabnormalresult
Acutechestsyndrome
Pneumonia
Atelectasis

Skeletalradiographs

Description
Radiologicfindingsofboneinfarctionarelocalizedtobonescontainingred
marrowtherefore,thepatternofosseouschangesisdifferentinchildrenand
adults
Inchildren,marrowispresentinallbones,includingthesmallbonesofthe
hand

Inadults,marrowislimitedtothebonesoftheaxialskeleton(ie,spine,
pelvis,skull,andthemostproximalportionofthefemurandhumerus)
Shouldonlybeusedwhenclinicallyindicated.Mostboneinfarctionsare
diagnosedclinicallyonthebasisofsymptoms(bonepain)andsigns(eg,
absenceoffever)

Advantages/disadvantages
Advantage:
Canconfirmthepresenceofboneinfarctions

Abnormal
Decreasedbonedensityresultingfromlossofboneowingtomarrowhyperplasia
Sparsetrabecularpatternwithwideseparation,resultinginawiremeshpattern
Boneinfarctions,asseenbyirregular,permeative,ormotheatendestruction
withoverlyingperiostealnewboneformation
Infants:seenpredominantlyinthesmallbonesofthehandsandfeet
Olderchildren:mostcommonintheepiphyses
Adults:incidenceofinfarctsinlongbonestendstoincreasewithage

Causeofabnormalresult
Skeletalalterationsarecausedbyerythroidhyperplasiaofthebonemarrow,whichfills
andexpandsthecancellousboneanddisturbsthetrabeculararchitecture.

TranscranialDopplerultrasound

Description
IntracranialvesselsareevaluatedbyDopplerflowstudiestohelpassesstherisk
ofstroke
Showntobepredictiveofstrokeinpediatricpatients
Iffindingssuggestthattheriskofstrokeiselevatedabovebaseline,childrenwith
sicklecelldiseasehavebeenfoundtobenefitgreatlyfromchronictransfusion
therapy.However,oncestartedinpatientsathighrisk,transfusionscannotlikely
besafelystopped

Advantages/disadvantages
Advantages:

Noninvasive
Assessescerebralbloodflow
Disadvantages:
Mustbeperformedbyaskilledtechniciandoneinconsultationwithaspecialist
Hasonlybeenshowntobepredictiveofstrokeinthepediatricpopulation

Normal
Velocitythroughtheintracranialarteries<200cm/s.

Abnormal
Increasedvelocitythroughtheintracranialarteries(>200cm/s).

Causeofabnormalresult
Narrowingofintracranialvesselsduetosludgingofabnormallyshapederythrocytesor
changesintheendothelialliningofthevessels.

Echocardiography

Description
Canbeusedtoassesscardiacfunctionaswellasgiveanestimateofpulmonary
pressures
Currentlyrecommendedforscreeningpatientsforpulmonaryhypertension
Tricuspidregurgitantvalues>2.5m/shavebeenassociatedwitha2year
mortalityrateof50%inpatientswithsicklecelldisease

Advantages/disadvantages
Advantages:
Noninvasive
Relativelyinexpensive
Disadvantages:
Notusefulfordeterminingpulmonarypressuresinapatientwhoisacutelyill,as
pulmonarypressuresincreaseinthissetting
Usedforscreeningonlyconfirmatorytestingwithrightheartcatheterization
and6minutewalktestisrequired

Abnormal
Tricuspidregurgitantjetvelocity>2.5m/s:diagnosticofpulmonary
hypertension
Tricuspidregurgitantjetvelocity>3.0m/s:moderatetoseverepulmonary
hypertension

Causeofabnormalresult
Pulmonaryhypertension.

MRI

Description
Imagingofthehipsandshouldersinparticularshouldbedonewhenpain
persistsforseveralweekstoevaluateforavascularnecrosis
Canalsobeusefulinthediagnosisofosteomyelitis

Advantages/disadvantages
Advantages:
Canaidindiagnosinganddeterminingtheextentofavascularnecrosis
Canbeusefulindiagnosingosteomyelitis
Disadvantages:
Cannotbetoleratedbypatientswhoareclaustrophobic
Cannotalwaysdifferentiateabonyinfarctfromosteomyelitis

Abnormal
IncreasedT2signalwithsurroundingdecreasedT1signalandcollapseand
flatteningofthearticularsurfaceisseeninpatientswithavascularnecrosis
BonemarrowedemaandT2hyperintensitycanbeseeninpatientswith
osteomyelitis

Causeofabnormalresult
Avascularnecrosis
Osteomyelitis

Bonescan

Description
Canbeusefulindiagnosingosteomyelitis.

Advantages/disadvantages
Advantages:
Highsensitivity
LessexpensivethanMRI
Disadvantages:
Lowspecificity
Timeconsuming

Abnormal
Radioactive'hotspot'canbeseeninpatientswithosteomyelitis.

Causeofabnormalresult
Osteomyelitis.

Abdominalultrasound

Description
Canbeusefulindeterminingthecauseofabdominalpain
Determiningthecauseorrightupperquadrantpaincanbeparticularlydifficult,
asthedifferentialdiagnosisisextensive

Advantages/disadvantages
Advantages:
Inexpensiveandreadilyavailable
Canbediagnostic,particularlyforgallstones
Disadvantages:
Mustbedonebyaskilledpractitioner
ResultsarenotasdetailedasthoseofCTscanorMRI

Abnormal
Presenceofgallstonesanddilatedductsinthesettingofpainonexamination

(canbediagnosticofcholecystitis)
Enlargingliverinthesettingofadecreasinghemoglobinlevel(cansuggest
hepaticsequestration)

Causeofabnormalresult
Cholelithiasis
Cholecystitis
Hepaticsequestration

Othertests

Retinalexamination

Description
Itisimportanttoexaminepatientsforocularcomplicationsofsicklecelldisease
annually,lookingforevidenceofneovascularization.Ifneovascularizationis
seen,laserphotocoagulationcanbeusedtopreventretinalhemorrhage
Patientsreportingnewonsetoffloatersshouldbeseenemergentlytolookfor
evidenceofretinalhemorrhage

Advantages/disadvantages
Advantage:
Canbeusedtodetermineifpatientsareatriskforretinalhemorrhage
Disadvantage:
Mustbedonebyaskilledpractitioner

Abnormal
Seafanformation,vascularproliferation
Retinalhemorrhage

Causeofabnormalresult
Sickleretinopathy.

Clinicalpearls
NeonatalscreeningforsicklecelldiseaseisnowdoneinallstatesintheU.S.
Patientswhoreportorpresentwithfever,increasedornewpain,orpainthatisnottypical

ofpreviousvasoocclusivecrisesshouldbethoroughlyevaluatedwithacomprehensive
history,physicalexamination,andfocusedlaboratorystudiessoasnottomissaserious
complication
Noobjectivelaboratorydatacandefinitivelyindicatethatapaincrisisisoccurring
Patientsoftendonotpresenttothehospitalwithacutechestsyndromebut,rather,with
severevasoocclusivecrisis.Suchpatientsneedtomonitoredcarefullyforsignsof
progressivehypoxia,andrepeatchestimagingmaybenecessaryifthepatient'sstatus
changes

Considerconsult
Referpatientswithbonepainthatisrefractorytostandardtherapy,associatedwithfever,or
atypicalforsicklecelldiseaseforradiographicinvestigation
Referpatientspresentingwithsevereabdominalpainforradiographicinvestigationand
laboratorystudies
ReferpatientsforMRIwhendiagnosticdoubtstillexistsafterclinicalexaminationand
radiographicinvestigationortoexcludeosteomyelitis,especiallyinpatientsinwhom
Salmonellainfectionissuspected

Treatment
Goals
Symptomcontrolandmanagementofdiseasecomplicationsarethemajorgoals.Theseinvolve:
Managementofpain,bothchronicandacute
Preventionandmanagementofacutecomplications
Managementofhemolyticanemia
Pharmacologicameliorationofdiseaseseverity
Prophylaxisagainstandprompttreatmentofinfection
Preventionofstroke
Geneticcounselingandrelevanthealthandnutritionaleducationforpatientsandrelatives

Immediateaction
Fluidreplacement:requiredimmediatelyformostpatients,whoaremildlydehydrated
owingtourineconcentratingdifficultiesfluidandelectrolytebalanceisalsooftendisrupted
duringpaincrisesandinfections,andthepatient'sconditionisexacerbatedbyinadequate

hydration
Milddehydration:intakeofanoralrehydrationsolutionshouldbeencouraged
supplementalintravenousfluidsmayberequiredifthepatientisunableorunwillingtotake
oralfluids
Severedehydration:shouldbetreatedthesameasshock,withisotonicfluidbolusesand
strictmeasurementofintakeandoutputintravenousfluidsshouldthenbegivenatarateof
atleast1.5timesthemaintenancerate
Keepinmindthataspatientsgetolder,theyaremorelikelytohavepulmonary
hypertension,sovolumestatusmustbevigilantlymonitoredduringvolumeresuscitation

Therapeuticoptions
Summaryoftherapies
Bonemarrowtransplantation(ZE0EB3EA_164_147)istheonlypotentiallycurativetreatment

forsicklecellanemia,butitisinfrequentlyusedduetothelackofasuitablebonemarrow
donor,highcost,andassociatedrisks(10%mortalityrateinchildren)
Bloodtransfusions(1020812)areindicatedinpatientswithacute,symptomatic(shortnessof

breath,chestpain)exacerbationsofanemiafollowingalifethreateningevent,suchas
stroke,acutechestsyndrome,andspleniccrisisand/orbeforehighriskprocedures,such
assurgery.Therearenodatatosuggestthattransfusionsarebeneficialinpatientswith
uncomplicatedpaincrises,andbloodtransfusionisnotadvocatedasafirstlineapproach
forpreventionofrecurrentpainfulcrises
Hydroxyurea(ZDE47DC2_68_5)increasestheproductionofHbF.InthepresenceofHbF,

HbScannotpolymerizeand,therefore,sicklingoftheerythrocytesdecreases.
Hydroxyureaisapprovedtoreducethefrequencyofpainfulcrisesandtheneedforblood
transfusionsinpatientswithrecurrentmoderatetoseverecrises.Managementguidelines
fromtheNationalHeart,Lung,andBloodInstitute(http://www.nhlbi.nih.gov/)recommendtheuse
ofhydroxyureainpatientswithHbSSdiseaseorHbSthalassemiawhohavethreeor
morepainfulcrisesperyearpatientswithacutechestsyndromeorotherlifethreatening
complicationsandpatientswithsevere,symptomaticanemia.Therearelimiteddataon
theuseofhydroxyureainpreventingstroke.Currentrecommendationsstilladvocatethe
useofchronictransfusiontherapytopreventstroke
Erythropoietinmayberequiredinpatientswithsicklecelldiseasewhodevelopendstage
renaldisease
Theuseofhydroxyureaanderythropoietinincombinationappearstobesafeinpatients
withsicklecelldisease.Thebenefitofcombinationtherapyisthatthetwoagentsnotonly
increaseHbS,aserythropoietinalonewoulddo,butincreaseHbFaswell

Inmostpatientswithsicklecelldisease,treatmentisaimedatavoidingvasoocclusive
crises,relievingchronicsymptoms,andpreventingacuteandlongtermcomplications
Healthmanagementinterventions
Preventionofinfection:
ProphylacticpenicillinVshouldbeadministeredfromtheageof2monthsuntilage5years
topreventseriousinfections,suchaspneumonia.Prophylaxisisusuallycontinueduntil
age6inpatientswhohavenothadaseverepneumococcalinfectionorundergone
splenectomypreviouslyandwhohaveacomprehensivecareplan
Immunizationwithpneumococcalvaccineshouldbegivenfromtheageof2monthsto

reducetheriskofpneumococcalinfection
Childrenshouldalsoreceiveinfluenzavaccinationat6monthsofageandannually
thereafter
Meningococcalpolysaccharidevaccinationisrecommendedforchildrenwithsplenic
dysfunctionat2yearsofage
Allroutineimmunizationsshouldbegiveninatimelyfashion
Adultsshouldreceiveinfluenzavaccinationyearlyandpneumococcalvaccinationevery5
years
Counselingandeducation(ZDD45DF8_32E_3CE):

Educationandguidanceshouldbeprovidedtopatientsandcaregivers
Caregiversshouldbetaughttobevigilantfortheearlysymptomsandsignsofserious
complications,includingpalpatingandmeasuringthespleentocheckforenlargement,
andshouldknowwhatactiontotakeifthepatientexperiencesanacutecrisis
Dietarysupplementation:
Childrenwithsicklecelldiseasecanreceiveironsupplementedformulaandcerealasdo
otherchildren.Noadditionalironsupplementationshouldbegivenunlessthereis
documentedirondeficiency
Patientswithsicklecelldiseasehaveanincreasedrequirementfordietaryfolicacid,which
shouldbegivendaily(especiallyimportantduringpregnancy)
Proteinsupplementsaresometimesgivenifweightgainisinadequateininfancyor
growthanddevelopmentaldelaysoccuratpuberty
Certainnutritionalsupplements,suchasarginine,arethoughttoreducetheriskofvaso

occlusivecrisishowever,evidencetosupporttheseclaimsislimited
Painmanagement:
Pain,bothchronicandacute(crisis),isthemostcommonanddebilitatingproblemin
patientswithsicklecelldisease.Treatmentsareaimedatalleviatingpainandreducing
thefrequencyofpainfulcrises
Comprehensivepainassessmentisrequiredtoguidetheselectionofanalgesic,and
frequentfollowupisnecessarytomaintainoptimalpainmanagement
Anageappropriatepainscalecanbeusedtoassessthelevelofpainandguidetreatment
options
Acetaminophen(withorwithoutcodeine)ornonsteroidalantiinflammatorydrugs(NSAIDs)
(173386958_976)areusedformildpain,ofteninconjunctionwithcomfortmeasures(eg,

heatingpads),andaregenerallysufficientforpainreliefinchildrenunderage6
Strongeropioids(59467)areusedformoderatetoseverepainandareusuallyrequiredin
olderchildrenandadults
Ifthepainissevere,parenteralopioidtherapymayberequiredmorphineisgenerally
preferred
Selfadministeredanalgesiamaybeallowedinolderchildren,adolescents,andadults
Transcutaneouselectricalnervestimulation(TENS)(1100858)isasafeandrelatively

noninvasiveinterventionthatcanbeusedtoalleviatemanydifferenttypesofpain
Otherpainmanagementstrategiesincludewarmcompresses,physicaltherapy,
hypnotherapy,biofeedback,andrelaxationtherapy,someofwhichmaybeavailableata
specialistpainclinic
Chronicconditions:
Legulcersmayrequiretreatmentwithbedrest,standardwoundcare,antibiotics,
debridement,painreliefmeasures,andskingraftsinsomecases
Cholelithiasismayrequiregallbladdersurgeryifthepresenceofgallstonesleadsto

gallbladderdisease
Priapismnecessitatesemergentconsultationwithaurologist.Treatmentincludes

intravenoushydration,supplementaloxygenfordocumentedhypoxia,andpainrelief
withparenteralopioids.Intracorporealinjectionofavasoactiveagentmaybeconsidered,
andaspirationandirrigationareusedifintracorporealinjectiondoesnotresultin
detumescence.Penileshuntshouldbeconsideredforpatientswithrefractoryepisodes

Managementofacutecrises
Complicationsofsicklecellanemiacanbesevereandacute,requiringimmediate
treatment,andmaybecomelifethreatening
Painfulcrisis,infection,acutesplenicsequestration,aplasticcrisis,acutechestsyndrome,
andstrokearethemajoracutecomplications
Fluidreplacementtherapy(59535)isusuallyrequired,asthefluidandelectrolytebalanceis

oftendisruptedduringpainfulcrisesandinfections,andtheconditionisexacerbatedby
inadequatehydration
Painfulcrisis:
Occursinalmostallpatientswithsicklecellanemiaandcanlasthourstodayssome
patientshaveoneepisodeeveryfewyears,whereasothershavemanyepisodesperyear
Canbesevereenoughtorequireadmissiontothehospitalforpaincontroland
intravenousfluidspatientsshouldbemonitoredcarefullyfordehydrationiforalintakeis
poor
Acetaminophen,NSAIDs,opioids,oracombinationoftheseagentsareused,depending
ontheseverityofthepain
Patientsshouldbecloselymonitoredduringpainfulcrisesfortheonsetofother
complications,particularlyacutechestsyndrome,whichmaydeveloprapidly
Generallyresolveswithin5to7dayshowever,asevereepisodemaycausepainthat
persistsforweeksorevenmonths
Hydroxyureacanamelioratetheclinicalcourseofsicklecellanemiainsomeadult
patientsexperiencingthreeormorepainfulcrisesperyear
Infection:
Childrenwithsicklecelldiseaseareparticularlysusceptibletoacuteinfections,sepsis,
andmeningitis
Childrenpresentingwithfever(temperature>38.5C[101.3F])shouldbeevaluated
thoroughly
Followingevaluation,childrenwhoarebelievedtobeatlowriskcanbegivenparenteral
antibiotics(ceftriaxone)andmanagedathomewithclosefollowup
Childrenathighriskorwhoappeartoxicshouldbegivenabroadspectrumparenteral
antibioticimmediately,andbloodculturesshouldbeobtainedandfurtherevaluation

carriedoutasappropriate
Theantibioticsusedshouldcoverencapsulatedorganisms,especiallyHaemophilus
influenzaeandS.pneumoniae
Inaddition,vancomycinshouldbeadministeredinchildreninwhombacterialmeningitisor
othersevereillnessesaresuspectedandinthosewholiveincommunitieswithahigh
incidenceofpenicillinresistantpneumococci
InfectionsthatareoftencausedbyS.aureusorSalmonellaspecies,suchasosteomyelitis,
shouldbetreatedinitiallywithabroadspectrumantibioticandvancomycin
Additionalantibioticsshouldbeselectedasappropriatebasedontheresultsofblood
cultures
Otheracutecomplications,suchasacutechestsyndrome,splenicsequestration,and
aplasticcrisis,shouldbeconsideredduringafebrileillness
Acutechestsyndrome:
Diagnosedinpatientswithfever,chestpain,andinfiltrateonchestradiograph
Earlyrecognitionandaggressivetreatmentwithsupplementaloxygen(ZDEECB23_9_171),
analgesics,antibiotics,andoftensimpleorexchangetransfusionsareessentialandmay
belifesaving
Childreninwhomacutechestsyndromeissuspectedshouldbereferredtoapediatric
intensivecareunitimmediatelyduetothepotentialforrapiddeteriorationtopulmonary
failureanddeath
Patientsmostatriskofdevelopingrespiratoryfailurearethosewithmultilobar
involvement,cardiacdiseaseatbaseline,andadecreaseinplateletcount
Splenicsequestration:
Severecasescanprogressrapidlytoshockanddeath,sopromptrecognitionand
immediatetreatmentarerequired
Bloodtransfusionsmaybelifesaving
Surgicalsplenectomytopreventrecurrencemayberecommendedinpatientswith
recurrentepisodesorafteralifethreateningcrisis
Aplasticcrisis:
OftencausedbyacuteinfectionwithhumanparvovirusB19(commonlywithoutthe
characteristicrash)

HumanparvovirusB19affectserythrocyteprecursors,resultinginreticulocytopenia,
which,alongwithongoinghemolysis,canbelifethreatening
Bloodtransfusionsaregivenuntilthereticulocytecountrecovers
Isolationfromvulnerableindividualsisessential,asparvovirusB19ishighlycontagious
Stroke:
Ischemicstrokeorintracranialhemorrhageisaparticularlydevastatingcomplicationthatis

commoninchildrenwithsicklecellanemia
ScreeningwithtranscranialDopplerultrasoundcanidentifypediatricpatientsathigh
riskforstrokewhomaybecandidatesforprimarystrokepreventionwithachronicblood
transfusionprogram
Treatmentofstrokeinchildrenwithsicklecelldiseaseincludeshydration,supportive
care,physicaltherapy,andchronictransfusions(every45weeks).Anticonvulsant
medicationmayalsobeindicated
Adultsshouldbeevaluatedfortheuseoftissueplasminogenactivatoriftreatmentis
beinginstitutedwithin3hoursofischemicstrokeonset
Useofchronictransfusiontherapytopreventstrokeinadultsremainscontroversial
Pulmonaryhypertension:

Definedasatricuspidregurgitantjetvelocity>2.5m/s
Foundin30%to40%ofadultswithsicklecelldiseaseassociatedwitha2yearmortality
rateof50%
Patientsinwhomscreeningechocardiographyshowsanelevatedtricuspidregurgitantjet
velocitycanbereferredforrightheartcatheterizationand/or6minutewalktest
Idealtherapyisunknown.Potentialtherapiesincludebosentan,sildenafil,transfusion,
andhydroxyurea.Furtherstudyisneededtodeterminetheefficacyofthesetherapiesin
patientswithsicklecelldisease
Newtreatments
Bonemarrowtransplantationhasbeeneffectiveinchildren,butduetoorgandamage,
adultswerenotconsideredtobeeligiblefortransplantation.Newtransplantprotocols
usingreducedintensitychemotherapeuticregimensarebeingevaluatedwiththegoalof
curingadultswithsicklecelldisease
StimulationofbonemarrowcellstoincreaseproductionofHbFisanotherpotential

treatmentstudiestodatehaveusedbutyrateandhydroxyureatoincreaseHbFlevels,
withpromisingresults
Genetherapy,eitherthroughsilencingofthedefectiveHBBgenesorbytransferringa
normalHBBgeneintostemcellsfromindividualswithsicklecellanemia,isbeing
exploredasapotentialcure.However,thereareconcernsregardingthesafetyand
reliabilityoftheprocedures.Researchintogenetherapyforsicklecellanemiaisstillin
veryearlystages

Guidelines
TheNationalHeart,Lung,andBloodInstitute(http://www.nhlbi.nih.gov/)hasproducedthefollowing:
TheManagementofSickleCellDisease
(http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf).NIHPublicationNo.022117.

Bethesda,MD:NationalHeart,Lung,andBloodInstitute2002
TheBritishSocietyforHaematology(http://www.bsh.org.uk/)hasproducedthefollowing:
ReesDC,OlujohungbeAD,ParkerNE,StephensAD,TelferP,WrightJBritish
CommitteeforStandardsinHaematologyGeneralHaematologyTaskForcebythe
SickleCellWorkingParty.Guidelinesforthemanagementoftheacutepainfulcrisisinsickle
celldisease(http://www.bcshguidelines.com/pdf/sicklecelldisease_0503.pdf).BrJHaematol.

2003120:74452
TheAmericanAcademyofFamilyPhysicians(http://www.aafp.org)haspublishedthefollowing:
WethersDL.Sicklecelldiseaseinchildhood.PartI.Laboratorydiagnosis,pathophysiologyand
healthmaintenance(http://www.aafp.org/afp/20000901/1013.html).AmFamPhysician.
200062:101320
WethersDL.Sicklecelldiseaseinchildhood:partII.Diagnosisandtreatmentofmajor
complicationsandrecentadvancesintreatment(http://www.aafp.org/afp/20000915/1309.html).

AmFamPhysician.200062:130914
YaleSH,NagibN,GuthrieT.Approachtothevasoocclusivecrisisinadultswithsicklecell
disease(http://www.aafp.org/afp/20000301/1349.html).AmFamPhysician.200061:1349

56

Orderoftherapies
Counselingandeducation(ZDD45DF8_32E_3CE)
PenicillinV(130279)
Acetaminophen(ZC45233E_2DB_38D)

NSAIDs(173386958_976)
Opioids(59467)
Fluidreplacementtherapy(59535)
Oxygen(ZDEECB23_9_171)
Hydroxyurea(ZDE47DC2_68_5)
Bloodtransfusions(1020812)
Folicacid(2392218)
Bonemarrowtransplantation(ZE0EB3EA_164_147)
TENS(1100858)

Efficacyoftherapies
Theonlypotentiallycurativetreatmentisbonemarrowtransplantation,butitsuseis
limitedbydonoravailabilityandthefunctionalclassofthepatient
Withallothertreatments,includingthosethatreducethefrequencyofcrises,themedian
ageatdeathis42yearsformenand48yearsforwomen
TENSisgenerallyconsideredtobeaneffective,safe,andrelativelynoninvasive
interventionthatcanbeusedtoalleviatemanydifferenttypesofpain
Analgesicsareeffectiveiftailoredtotheindividualpatientbasedonrigorouspain
assessmentandfollowup
ProphylacticpenicillinVsubstantiallylowerstheriskofinvasivepneumococcalinfection
Heptavalentconjugatedpneumococcalvaccineand23valentunconjugated
pneumococcalvaccinehaveanefficacyagainstpneumococcalinfectionofatleast85%
and56%to81%,respectively
Hydroxyureacanamelioratetheclinicalcourseofsicklecellanemiainsomeadult
patientsexperiencingthreeormorepainfulcrisesperyear

Medicationsandothertherapies
Medications

PenicillinV

Pharmacology

Penicillinantibioticbactericidalnarrowspectruminhibitsbacterialcellwall
peptidoglycansynthesis.

Indication
Prophylaxisagainstpneumococcalinfectionfromthetimeofdiagnosisto6years
ofage
Offlabelindication

Prescribing
Prescriptiononly.

Doseanddoseinformation
Pediatric
Oral:
Underage3:125mgevery12hours
Overage3:250mgevery12hours
Treatmentcourse:fromthetimeofdiagnosisto6yearsofage
recommendationsonwhentodiscontinueprophylaxisaremixeddueto
concernsregardingfunctionalasplenia

Hepatic/renalimpairment
Usecautionwithhighdosesorparenteraladministrationinpatientswithrenal
impairmentrashesaremorecommonadosereductionmaybenecessary.

Administration
Dosesshouldbetakenahalfhourto1hourbeforefoodoronanempty
stomach
Shakeoralsuspensionswellbeforeuse.Refrigerateat2to8C(35.646.4F)
donotfreeze.Discardcontentsasinstructedafteropening

Contraindications
Hypersensitivitytopenicillinsoranyothercomponent.

Cautions
Seriousandfatalhypersensitivityreactions,includinganaphylaxis,havebeen
reported.Usecautioninpatientswithahistoryofsensitivitytomultiple
allergensorprevioushypersensitivitytocephalosporins

Riskofmildorlifethreateningpseudomembranouscolitis.Considerthe
diagnosisinpatientspresentingwithdiarrhea.Usecautioninpatientswitha
historyofgastrointestinaldisease,particularlycolitis

Monitor
LFTresults(withprolongedtherapy)
Renalfunction(withprolongedtherapy)
CBC(withprolongedtherapy)

Adverseeffects
Common:diarrhea,nausea,rash,urticaria,superinfection
Rare:exfoliativedermatitis,pseudomembranouscolitis,angioedema,interstitial
nephritis,serumsicknesslikesyndrome,blooddyscrasias,electrolyte
disturbances,hemolyticanemia,StevensJohnsonsyndrome,neurotoxicity,
nephropathy,bleeding,cholestatichepatitis
Hypersensitivityreactions,includinganaphylaxisandbronchospasm,havebeen
reported

Interactions
Coumarins(theoreticalriskofchangesinINR)
Methotrexate(increasedserummethotrexatelevel)
Probenecid(reducedexcretionofpenicillins)

Patientandcaregiverinformation
Reportsignsandsymptomsofhypersensitivityreactions,anaphylaxis,
pseudomembranouscolitis,hepaticdysfunction,orrashtophysician
immediately
Regularbloodandlaboratorytestsmayberequiredduringlongtermtherapy

Evidence
AsystematicreviewincludedthreeRCTsofprophylacticantibioticregimensfor
preventingpneumococcalinfectioninchildrenwithsicklecelldisease.Allthree
trialsfoundthatprophylacticpenicillinsignificantlyreducedtheriskof
pneumococcalinfectionandwasassociatedwithminimaladversereactions[1]
LevelA

References

[1]

Acetaminophen

Pharmacology
Analgesicantipyreticnonnarcoticanalgesicinhibitsprostaglandinsynthesisinthe
centralnervoussystem(CNS)andperipherallyblockspainimpulsegeneration.

Indication
Treatmentofmildpain.

Prescribing
Availableoverthecounter
Availableincombinationpreparationswithcodeine

Doseanddoseinformation
Adult
Oral:500to1,000mgevery4to6hours,asneededmaximum:4g/d.

Pediatric
Oral:10to15mg/kg/doseevery4to6hours,asneededmaximum,90mg/kg/d.

Elderly
Doseselectionintheelderlyshouldbecautious,usuallystartingatthelowendof
thedosingrange.Thisreflectsthegreaterfrequencyofdecreasedhepatic,renal,or
cardiacfunctionandconcomitantdiseasesandmedications.

Hepatic/renalimpairment
Usecautioninpatientswithhepaticandrenalimpairmentadosereductionmaybe
necessary.

Contraindications
Hypersensitivitytoacetaminophenoranyothercomponent.

Cautions
Reportsofhepaticandrenaldamagewithoverdose.Unlesstreatedpromptly,
overdosemayleadtopotentiallyfatalmultiorganfailure.Accidentaloverdose
canoccurifoverthecounterpreparationscontainingacetaminophenaretaken
alongwithprescriptionmedicationscontainingacetaminophen

Usecautionwithalcoholconsumption(>3drinksperday)

Adverseeffects
Common:nausea,vomiting,rash
Rare:blooddyscrasias
Overdose:acutepancreatitis,acutehepaticandrenalfailure,confusion,delirium,
vascularcollapse,convulsions,coma,jaundice
Hypersensitivityreactions,includingurticariaandangioedema,havebeen
reportedrarely

Interactions
Alcohol(increasedriskofhepatotoxicity)
Anticoagulants(enhancedanticoagulanteffect)
Anticonvulsants(increasedriskofhepatotoxicity)
Barbiturates(increasedriskofhepatotoxicity)
Cholestyramine(decreasedabsorptionofacetaminophen)
Colestipol(decreasedabsorptionofacetaminophen)
Domperidone(increasedabsorptionofacetaminophen)
Isoniazid(increasedserumacetaminophenlevel)
Metoclopramide(increasedabsorptionofacetaminophen)
Rifampin(increasedriskofhepatotoxicity)

Pregnancyandlactation
Consideredsafeforshorttermuseduringpregnancy
Compatiblewithlactation

Pregnancycategory
PregnancycategoryB.

Patientandcaregiverinformation
Avoidconsumingalcoholduringtherapy
Donottakewithotheracetaminophencontainingpreparations

Interactionswithothermedicationsarepossible.Consultphysicianor
pharmacistbeforetakingotherprescription,complementaryandalternative
(includingherbal),oroverthecountermedications

NSAIDs

Pharmacology
Antiinflammatoryantipyreticanalgesicinhibitsprostaglandinsynthesisby
inhibitionofcyclooxygenase(COX)enzymenonspecificNSAIDsinhibitbothCOX1
andCOX2isoforms.

Indication
Treatmentofmildtomoderatepain.

Prescribing
Ibuprofenandnaproxenareavailableoverthecounter
Ketorolacisavailablebyprescriptiononly

Doseanddoseinformation
Adult
Ibuprofen:

Oral:200to800mgevery6to8hours,asneededmaximum,3,200mg/d
Naproxen:

Oral:500mginitiallyfollowedby250mgevery8to12hours,asneeded
maximum,1.25g/d
Ketorolac:

Intramuscular:30to60mginitiallyfollowedby15to30mgevery6to8
hours,asneededmaximum,120mg/dfor5days

Pediatric
Ibuprofen:

Oral:10mg/kg/doseevery6to8hours,asneededmaximum,40mg/kg/d
Naproxen:

Oral:10mg/kg/dindivideddosesevery12hours,asneeded

Elderly
Usecautionintheelderlyincreasedriskofseriousadverseeffectsandincreased
susceptibilitytorenalaccumulationduetodecreasingrenalfunctionwithage.
Clinicallysignificantulceration,bleeding,andfatalgastrointestinaleventscanoccur
insomeelderlypatients.

Hepatic/renalimpairment
Usecautioninpatientswithmildhepaticimpairmentadosereductionmay
benecessary.Avoidinpatientswithseverehepaticimpairmentdueto
increasedriskofbleeding
Usecautioninpatientswithmildrenalimpairmentmayleadtodeterioration
ofrenalfunctionandpossiblyrenalfailureadosereductionmaybe
necessary.Avoidinpatientswithmoderatetosevererenalimpairmentdueto
increasedriskofNSAIDinducedrenalimpairment
Ketorolaciscontraindicatedinpatientswithrenalimpairment

Administration
Oraldosesshouldbetakenwithorafterfoodtominimizetheincidenceof
gastrointestinaladverseeffects
Followintramuscularadministrationguidelinestopreventadverseeffects
(ketorolac)

Contraindications
HypersensitivitytoNSAIDsoranyothercomponent
'Aspirintriad'
Treatmentofperioperativepaininthesettingofcoronaryarterybypassgraft
surgery
Ketorolac:
Activeorrecentgastrointestinalbleedingorulceration
Severerenalimpairmentorhypovolemia
Cerebrovascularbleedingorotherbleedingdisorders
Preoperativeorintraoperativeuse(increasedriskofbleeding)
Intrathecalorepiduraluse(duetoalcoholcontentofformulation)

Laboranddelivery
Lactation
Concomitantusewithaspirin,otherNSAIDs,5aminosalicylicacidderivatives,
orprobenecid
Useafterplasticsurgeryorneurosurgery

Cautions
Maycauseanincreasedriskofseriouscardiovascularthromboticevents,
includingmyocardialinfarctionandstroke.Riskmayincreasewithdurationof
useorinpatientswithcardiovasculardiseaseorriskfactorsforcardiovascular
disease.Usecautioninpatientswithhypertension,fluidretention,andheart
failuremonitorforadverseeffects
Maycauseanincreasedriskofseriousgastrointestinaladverseevents,including
bleeding,ulceration,andperforationofthestomachorintestines,whichmaybe
fatal.Riskincreaseswithlongerdurationofuse,concomitantusewith
corticosteroidsoranticoagulants,smoking,alcoholuse,advancedage,and
generalhealthstatus.Useextremecautioninpatientswithaprevioushistoryof
gastrointestinalbleedingorulceration,andmonitorforadverseeffects
Riskofseriousandpotentiallyfatalskinreactions,includingStevensJohnson
syndromeandtoxicepidermalnecrosis.Discontinuetherapyatfirstsignofrash
Reportsofrenalpapillarynecrosisandotherrenalinjurywithlongterm
administration
Riskofrenalimpairmentaftersurgery(especiallyifdehydrationorrenal
hypoperfusionexists)andbleeding(withnonselectiveNSAIDs),owingto
antiplateleteffects.Discontinuetreatmentbeforesurgery
KetorolacisapotentNSAIDthatisassociatedwithseriousriskswhenused
inappropriately.Onlyuseintheshortterm(upto5days)forpostoperativepain.
Usecautioninpediatricpatientsaftertonsillectomy
Chewableibuprofentabletsmaycausesevereorpersistentsorethroatorsore
throataccompaniedbyhighfever,headache,nausea,andvomiting.Donotuse
formorethan2daysoradministerinchildrenunderage3
Usecautioninpatientswithdehydrationorhypovolemia(shouldbecorrected
beforetreatmentbegins),asthmaorotherallergicdisorders,andcoagulation
disorders

Monitor
Renalfunction
CBC(withlongtermuse)
Liverfunctiontest(LFT)results(withlongtermuse)
Ophthalmicexaminationfindings(withlongtermuse)

Adverseeffects
Common:gastrointestinaldiscomfort,nausea,diarrhea,headache,dizziness,
dyspepsia,saltandfluidretention,elevatedLFTresultsinjectionsitereactions
(ketorolac)
Rare:gastrointestinalulcerationorbleeding,anemia,thrombocytopenia,
neutropenia,eosinophilia,agranulocytosis,hepatotoxicity,hyperkalemia,
tinnitus,depression,insomnia,interstitialnephritis,renalfailure,nephrotic
syndrome,hematuria,congestiveheartfailure,photosensitivity,alveolitis,
pancreatitis,StevensJohnsonsyndrome,toxicepidermalnecrolysis,colitis,
asepticmeningitis,blurredvision
Hypersensitivityreactions,includingfever,angioedema,bronchospasm,and
rashes,havebeenreportedrarely

Interactions
Angiotensinconvertingenzymeinhibitors(increasedriskofrenalimpairment
andhyperkalemia)
AngiotensinIIreceptorantagonists(increasedriskofrenalimpairmentand
hyperkalemia)
Anticoagulants(mayenhanceanticoagulanteffects,especiallywithnonselective
NSAIDs)
Antihypertensives(antagonismofhypotensiveeffect)
Antiplateletagents(increasedriskofbleeding)
Aspirin(increasedriskofadverseeffectswithconcomitantuse)
Baclofen(increasedserumbaclofenlevels)
Corticosteroids(increasedriskofgastrointestinalbleeding/ulceration)
Cyclosporine(increasedriskofnephrotoxicity)

Diazoxide(antagonismofhypotensiveeffect)
Digoxin(possibleincreasedserumdigoxinlevels)
Diuretics(increasedriskofnephrotoxicityandhyperkalemiaantagonismof
diureticeffect)
Lithium(increasedserumlithiumlevels)
Methotrexate(increasedserummethotrexatelevels)
Penicillamine(increasedriskofnephrotoxicity)
Phenytoin(increasedserumphenytoinlevels)
Potassium(increasedriskofhyperkalemia)
Probenecid(increasedserumketorolacandnaproxenlevels)
Quinolones(possibleincreasedriskofconvulsions)
Ritonavir(possibleincreasedserumNSAIDlevel)
Selectiveserotoninreuptakeinhibitors(increasedriskofbleeding)
Sibutramine(increasedriskofbleeding)
Sulfonylureas(possiblyenhanceseffectsofsulfonylureas)
Tacrolimus(increasedriskofnephrotoxicity)
Zidovudine(increasedriskofhematologictoxicity)

Pregnancyandlactation
Avoiduseduringpregnancywhenpossible.Useinthefirsttrimesterhasbeen
associatedwithahigherriskofmiscarriage,anduseinthethirdtrimestermay
causeprematureclosureoftheductusarteriosus,fetalrenalimpairment,
inhibitionofplateletaggregation,anddelayedlaborandbirth
Usecautionduringlactationshortacting,highlyproteinboundNSAIDs,such
asibuprofenanddiclofenac,arepreferred

Pregnancycategory
PregnancycategoryB(ibuprofen,naproxen)
PregnancycategoryC(ketorolac)

PregnancycategoryD(allNSAIDsinthethirdtrimester)

Patientandcaregiverinformation
Discontinuetherapypriortosurgery
Maycausedizzinessorsedationthatimpairsmentalalertnessand/or
coordination.Ifaffected,donotdrive,operatemachinery,orparticipatein
hazardousactivities
Maycausephotosensitivity.Avoidprolongedorexcessiveexposuretonaturalor
artificialsunlight,ortakeadequateprecautionsinthesun
Beawareoftheincreasedriskofseriouscardiovascular,gastrointestinal,and
dermatologicadverseeffects,andreportsignsandsymptomsofrashes,
gastrointestinalbleedingorpain(includingbloodinstool),visionchanges,blood
dyscrasias,hepatotoxicity,orcardiovasculareventstophysicianimmediately
Avoidconsumingalcoholduringtherapy
Interactionswithothermedicationsarepossible.Consultphysicianor
pharmacistbeforetakingotherprescription,complementaryandalternative
(includingherbal),oroverthecountermedications
Regularbloodandlaboratorytestsarerequiredwithprolongedtherapy

Evidence
Arandomized,controlledtrial(RCT)comparedketorolacversusparenteral
meperidinein20patientsaged11to19yearswithvasoocclusivecrisis.Ketorolac
wassignificantlymoreeffectiveatreducingpainboth30minutesand150
minutesafteradministration.Therewasnosignificantdifferencebetween
treatmentsintermsofthepercentageofpainfreepatientsat150minutes,
althoughthestudywastoosmalltoruleoutaclinicallysignificantdifference[2]
LevelB
AnRCTcomparedasingledoseofketorolacplusrepeateddosesofintravenous
meperidineversusasingleadministrationofplaceboplusrepeateddosesof
intravenousmeperidineinadultpatientswithvasoocclusivecrisis.No
significantdifferenceintermsofpainreliefwasfoundbetweenthetworegimens
[3]LevelB

However,anotherRCTinpatientsoverage14withvasoocclusivecrisisfound
thatintravenousketorolacwasmoreeffectivethanplaceboasasupplementto
repeateddosesofmeperidine,withthepatientsreceivingketorolacrequiring
significantlyloweramountsofmeperidinetocontrolpainthanthosereceiving

placebo[4]LevelB
AnRCTcomparedintravenousketorolacplusparenteralmorphineversus
placeboplusparenteralmorphineinchildrenandadolescentsaged5to17years
withvasoocclusivecrisis.Nosignificantdifferencesintheproportionofpatients
requiringhospitaladmissionforfurtherpainmanagementorintheneedfor
morphinewerefoundbetweenthegroups[5]LevelB

References
[2],[3],[4],[5]

Opioids

Pharmacology
Analgesicmimicendogenousopioidsbyactivatingopioidreceptorsinthecentraland
peripheralnervoussysteminhibitreleaseofneurotransmittersandactionat
postsynapticneurons,preventingtransmissionofpainimpulses.

Indication
Codeineisusedforthetreatmentofmildtomoderatepain
Otheropioidsareusedforthetreatmentofmoderatetoseverepain

Prescribing
Prescriptiononly
ControlledsubstancecategoryII:highpotentialforabuse
Codeineisavailableincombinationpreparationswithacetaminophen

Doseanddoseinformation
Adult
Codeine:

Oral:15to60mgevery4hours,asneeded
Hydromorphone:

Oral(immediaterelease):2to4mgevery3to4hours,asneeded
Morphine:

Intramuscularorintravenous:2.5to20mg/doseevery2to6hours,asneeded

Oral(immediaterelease):15to30mgevery4hours,asneeded
Oral(controlledrelease):15to30mgevery8to12hours,asneeded
Oxycodone:

Oral(immediaterelease):5to10mgevery3to4hours,asneeded

Pediatric
Codeine:

Oral:0.5to1mg/kg/doseevery4to6hours,asneededmaximum,60
mg/dose
Hydromorphone:

Intravenous:0.015mg/kg/doseevery4hours,asneeded
Morphine:

Intramuscularorintravenous:0.1to0.2mg/kg/doseevery2to4hours,as
neededmaximum,15mg/dose
Oral(immediaterelease):0.2to0.5mg/kg/doseevery4to6hours,asneeded

Elderly
Doseselectionintheelderlyshouldbecautious,usuallystartingatthelowend
ofthedosingrange.Thisreflectsthegreaterfrequencyofdecreasedhepatic,
renal,orcardiacfunctionandconcomitantdiseasesandmedications
Usecautionintheelderlyincreasedriskofadverseeffects.Clinically
significanttolerancecanoccurinsomeelderlypatients

Hepatic/renalimpairment
Usecautioninpatientswithhepaticimpairmentadosereductionis
necessaryincreasedriskofcoma
Usecautioninpatientswithmoderatetosevererenalimpairmentadose
reductionisnecessary

Administration
Doseshouldbestartedlowandadjustedaccordingtothepatient'sresponse
andtolerance.Maintainattheminimumeffectivedose
Doseshouldbegraduallyreducedbeforeceasingtherapy.Donotstop

treatmentabruptlyriskofwithdrawalsyndrome
Oraldosesshouldbetakenwithorafterfoodtominimizetheincidenceof
gastrointestinaladverseeffects
Sustainedreleasepreparationsshouldbeswallowedwholedonotcrushor
chew
Followparenteraladministrationguidelines(methodandrateof
administration)topreventadverseeffects

Contraindications
Hypersensitivitytoopioidsoranyothercomponent
Severerespiratorydepressionorcoma
Gastrointestinalobstruction,includingparalyticileus
Respiratorydepressionintheabsenceofresuscitativeequipment
(hydromorphone)
Statusasthmaticus(hydromorphone)
Obstetricanalgesia(hydromorphone)
Acutealcoholism(morphine)
Bronchialasthma(morphine,oxycodone)
Increasedintracranialpressure(morphine,oxycodone)
Respiratorydepression(morphine,oxycodone)

Cautions
Reportsofrespiratorydepression.Usecautionindebilitatedpatientsandin
thosereceivingconcomitanttherapywithotherCNSdepressants.Useextreme
cautioninpatientswithrespiratorydisorders,includingchronicobstructive
pulmonarydiseaseandasthma
Respiratorydepressanteffectsofopioidsmaybeexaggeratedinthepresenceof
headinjuries.Useextremecautioninpatientswithheadinjuriesorincreased
intracranialpressure
Mayobscurethediagnosisorclinicalcourseofacuteabdominalconditions.
Avoidinpatientswithgastrointestinalobstruction

MaycausespasmsofthesphincterofOddi.Usecautioninpatientswithbiliary
tractdisease,includingacutepancreatitis
Riskoftoleranceorpsychologicalandphysicaldependencewithprolonged
administration.Doseshouldbedecreasedgraduallybeforeceasingtherapyto
decreasetheriskofwithdrawalsyndrome
Riskofabuse.Usecautioninpatientswithahistoryofsubstancemisuse
Maycauseseverevasodilationandhypotensioninpatientswithcompromised
abilitytomaintainbloodpressure.Usecautioninpatientswithcardiovascular
disorders,includingarrhythmiasandhypotension
Reportsofincreasedriskofsuicidality,worseningdepression,anddepressive
behavior.Patientswithdepressionreceivingopioidsshouldbecloselyobserved
forclinicalworseningorsuicidality,especiallyatthebeginningoftreatmentorat
thetimeofdosechanges(codeine)
Usecautioninpatientswithhypothyroidism,Addison'sdisease,shock,prostatic
hypertrophy,alcoholism,urethralstricture,myastheniagravis,toxicpsychosis,
deliriumtremens,sicklecellanemia,andpheochromocytoma

Monitor
Respiratoryrate
Heartrate
Bloodpressure

Adverseeffects
Common:nausea,vomiting,constipation,sedation,drymouth,miosis,
orthostatichypotension(morecommonwithintravenousadministration),rash,
pruritus
Rare:respiratorydepression(doserelated),seizures,tremor,hallucinations,
confusion,arrhythmias,uretericorbiliaryspasm,hypothermia,increased
intracranialpressure,urinaryretention,flushing,elevatedLFTresults,moodand
libidochanges,musclerigidity(withhighdosesorintravenousadministration),
euphoria,circulatorycollapse,rhabdomyolysis(withoverdose),injectionsite
reactions
Hypersensitivityreactions,includinganaphylaxis,havebeenreportedrarely

Interactions

ConcomitantuseoffentanylandpotentcytochromeP4503A4inhibitors(eg,
ketoconazole,ritonavir,itraconazole,clarithromycin,nefazodone)mayresultinan
increaseinserumfentanyllevelsmonitorpatients,andadjustdoseifnecessary.Other
interactionsinclude:
Alcohol(enhancedhypotensiveandsedativeeffects)
Anticholinergics(concomitantusemaycauseparalyticileus)
Anticoagulants(prolongedusemayincreasetheinternationalnormalizedratio
[INR])
Antidepressants,tricyclic(enhancedsedativeeffect)
Antipsychotics(enhancedhypotensiveandsedativeeffects)
Antivirals(enhancedrespiratoryandCNSdepression)
Anxiolytics(enhancedsedativeeffect)
Carbamazepine(decreasedserumopioidlevel)
Cimetidine(increasedserumopioidlevel)
Ciprofloxacin(decreasedserumciprofloxacinlevel)
Hypnotics(enhancedsedativeeffect)
Metoclopramide(antagonismofmetoclopramideeffect)
Monoamineoxidaseinhibitors(CNSexcitationordepressionavoidconcomitant
useandfor14daysafterstoppingmonoamineoxidaseinhibitors)
Naloxone(mayprecipitateopioidwithdrawal)
Selectiveserotoninreuptakeinhibitors(enhancedsedativeeffectandincreased
riskofCNStoxicity)
Selegiline(hyperpyrexiaandCNStoxicity)

Pregnancyandlactation
Possibleassociationbetweenopioiduseinthefirsttrimesterofpregnancyand
fetalinguinalhernia.Cautionisrequiredduringlaborduetotheriskofneonatal
respiratorydepression.Withdrawaleffectsmayoccurinneonatesofdependent
mothers
Compatiblewithlactation

Pregnancycategory
PregnancycategoryC.

Patientandcaregiverinformation
Maycausedizzinessandsedationthatimpairsmentalcoordination.Donot
drive,operateheavymachinery,orparticipateinhazardousactivitiesifaffected
Maycauseorthostatichypotension.Takecarewhenchangingpositionfromlying
tosittingorfromsittingtostanding
Mayproducepsychologicalandphysicaldependence.Consultphysicianbefore
increasingdoseordiscontinuing.Doseshouldbetaperedgraduallybefore
ceasingtherapytopreventwithdrawalsyndrome
Increasedriskofconstipation
MayenhanceresponsetootherCNSdepressants,includingalcohol.Donot
consumealcoholduringtherapy
Reportsignsandsymptomsofrespiratorydepressiontophysicianimmediately
Interactionswithothermedications.Consultaphysicianorpharmacistbefore
takingotherprescription,complementaryandalternative(includingherbal),or
overthecountermedications

Evidence
AnRCTcomparedoralcontrolledreleasemorphineplusintravenousplacebo
versusintravenousmorphineplusoralplaceboinchildrenandadolescentsaged
5to17yearswithpainfulcrisesassociatedwithsicklecelldisease.Bothgroups
receivedaloadingdoseofintravenousmorphine.Therewerenosignificant
differencesinfrequencyofrescueanalgesia,durationofpain,orfrequencyof
spontaneouslyreportedadverseeventsbetweenthegroups[6]LevelA

References
[6]

Oxygen

Indication
Usedaspartofsupportivetreatmentforpatientswithhypoxia.

Contraindications
Chronicobstructivepulmonarydisease

Openflames

Cautions
Anyfireorsparkishighlydangerousinthepresenceofincreasedoxygen
concentrations,especiallywhenoxygenisusedunderpressure
Useofoxygentherapycanbedangerousincertainpatientswithchronic
obstructivepulmonarydiseasewhorelyontheirhypoxicdriveforstimulationof
respiration.Oxygentherapyshouldbeadministeredunderthesupervisionofan
experiencedphysicianinpatientswithanytendencytohypercapnia

Interactions
Noknownclinicallysignificantinteractions.Useofrespiratorysuppressantsand
sedativesshouldbeavoided.

Hydroxyurea

Pharmacology
InterfereswithsynthesisofDNAduringthesynthesisphaseofcelldivisionwithout
interferingwithribonucleicacid(RNA)synthesisinhibitsribonucleosidediphosphate
reductase,preventingconversionofribonucleotidestodeoxyribonucleotidesexact
mechanismofactioninpatientswithsicklecellanemiaisunknown.

Indication
Reducesthefrequencyofpainfulcrisesandtheneedforbloodtransfusionsin
patientswithrecurrent,moderatetoseverepainfulcrises
ANationalInstitutesofHealthconsensuspanelontheuseofhydroxyureain
sicklecelldiseaseconcludedthathydroxyureawasamajoradvanceinthe
treatmentofsicklecelldiseaseandthatthereisstrongevidencetosupportitsuse
inadults.Evidenceforuseinchildrenisnotasstrong,butemergingdataare
encouraging

Prescribing
Prescriptiononly
Cytotoxicmedication

Doseanddoseinformation
Adult

Oral:15mg/kg/dincreasedosein5mg/kg/dincrementsevery12weeksaccording
tobloodtestresults(maximallytolerateddosedefinedasaleukocytecountof
2,500/mm3inallstudies)maximum,35mg/kg/d.

Pediatric
Safetyandefficacyinpediatricpatientshavenotbeenestablished,butthe
medicationiscommonlyusedinthispopulation.Refertoadultdose.

Hepatic/renalimpairment
Usecautioninpatientswithhepaticimpairmentadosereductionmaybe
necessary
Usecautioninpatientswithrenalimpairmentadosereductionisnecessary

Administration
Followproceduresforproperhandlinganddisposalofcytotoxicagents
Contentsofcapsulemaybegiveninsoftfoodorliquid

Contraindications
Hypersensitivitytohydroxyureaoranyothercomponent
Markedbonemarrowsuppression(ie,leukopenia,thrombocytopenia,orsevere
anemia)

Cautions
Reportsofsevereorlifethreateningadverseeffectsrelatedtobonemarrow
suppression.Donotuseinpatientswithpreexistingsuppressedbonemarrow
function.Supplementationwithfolicacidisrecommendedforprophylaxis
Reportsoffatalandnonfatalpancreatitis,hepatotoxicity,andperipheral
neuropathyinpatientswithhumanimmunodeficiencyvirus(HIV)infection
receivingdidanosineand/orstavudineorotherantiretroviralagents.Monitor
patientsforsignsandsymptoms
Reportsofgenotoxicity.Longtermtreatmentformyeloproliferativedisorders,
suchaspolycythemiaveraandthrombocythemia,islikelyassociatedwith
secondarymalignancies

Monitor
CBC
Renalfunction

LFTresults

Adverseeffects
Common:myelosuppression,edema,drowsiness(withhighdoses),headache,
dizziness,rash,gastrointestinaldisturbances,macrocytosis
Rare:pancreatitis,hepatotoxicity,hepaticfailure,genotoxicity,secondary
leukemias,megaloblasticerythropoiesis,hemolysis,hyperbilirubinemia,
peripheralneuropathy,skincancer,renaldysfunction,pulmonaryinfiltrates,
elevatedLFTresults,hyperuricemia
Theriskofleukemiainpatientswithsicklecellanemiaisunclear.Thelongest
publishedfollowupstudywas9years.Inthisstudy,therewasnoincreasein
malignancyinpatientsreceivinghydroxyureaforsicklecellanemia.Another
morerecentstudyofpatientswithsicklecelldiseasereceivinghydroxyureafora
medianof8yearsalsoshowednoevidenceofanincreasedriskofmalignancy.
Longerfollowupisnecessarytoseeifuseinthispatientpopulationisassociated
withanincreasedriskofmalignancy

Interactions
Didanosine(increasedriskofpancreatitis,hepatotoxicity,andhepaticfailure
avoidconcomitantuse)
Fluorouracil(increasedriskofneurotoxicity)
Stavudine(increasedriskofpancreatitis,hepatotoxicity,andhepaticfailure
avoidconcomitantuse)
Zalcitabine(increasedriskofsynergisticantiretroviraleffect)
Zidovudine(increasedriskofsynergisticantiretroviraleffect)

Pregnancyandlactation
Notrecommendedforuseduringpregnancyduetopossibleteratogeniceffects
Avoiduseduringlactation

Pregnancycategory
PregnancycategoryD.

Patientandcaregiverinformation
Increasedriskofblooddyscrasiasandsecondarymalignancies
Reportsignsandsymptomsofmyelosuppressiontophysicianimmediately

Regularbloodorlaboratorytestsarerequiredduringtherapy

Evidence
Asystematicreviewofrandomizedorquasirandomized,controlledtrialsof
hydroxyureaversusplacebo,standardtherapy,orotherinterventionsfor1
monthorlongeridentifiedtwotrialsinvolvingatotalof324adultsandchildren.
Onlyonetrial,involving299adultswithseveresicklecelldisease,metthe
inclusioncriteria.Thetrialfoundthattreatmentwithhydroxyurearesultedina
significantdecreaseintheannualcrisisrate,useoftransfusions,andlife
threateningcomplications(inparticular,acutechestsyndrome)comparedwith
placebo[7]LevelA
AsystematicreviewofoneRCTand12observationalstudiesshowedthat
patientswithsicklecelldiseasereceivinghydroxyureahadfewerpainfulcrises
andhospitaladmissionsandhigherconcentrationsofHbF.Therewasno
convincingevidencethattreatmentwithhydroxyureawasassociatedwiththe
developmentofleukemiaorlegulcers,anddatawereinsufficienttocalculatethe
riskforskinneoplasms[8]LevelA
AsystematicreviewofoneRCT,22observationalstudies,and3casereports
showedthatthattreatmentwithhydroxyureadecreasedthenumberofhospital
admissionsandincreasedtotalhemoglobinandHbFlevelsinchildrenwith
sicklecelldisease.However,toofewchildrenwereenrolledinlongtermstudies
tostateanythingdefinitiveregardingtheadverseeffectsofhydroxyureainthe
pediatricpopulation[9]LevelA
AnRCTin34patientswithsicklecellanemiaand296patientswithHbS
thalassemiashowedthattreatmentwithhydroxyurearesultedinareductionin
painfulcrises,acutechestsyndrome,transfusionrequirements,andhospital
admissionsandimprovedsurvivalatamedianfollowupof5to8years.Baseline
HbFlevelsandpercentagechangeinserumlactatedehydrogenasebetween
baselineand6monthspredictedsurvivalinpatientsreceivinghydroxyurea[10]
LevelA
Alongterm,observationalfollowupstudyofadultpatientswithsicklecell
anemiawhoparticipatedinanRCToftheeffectsofhydroxyureaonvaso
occlusiveeventsfrom1992to1995foundthattheuseofhydroxyureafor
frequentpainfulcrisesappearedtoresultinareducedmortalityrateafter9years
offollowup.SurvivalwasrelatedtoHbFlevelsandthefrequencyofvaso
occlusiveevents[11]LevelB

References
[7],[8],[9],[10],[11]

Herbalmedicines,vitamins,andminerals

Folicacid

Pharmacology
Bgroupvitaminrequiredforpurineandpyrimidinebase(DNA)synthesis,amino
acidmetabolism,andnormalerythropoiesisinvolvedinmaturationofrapidly
proliferatingtissuesinvolvedinembryonicneuraltubeclosure.

Indication
Patientswithsicklecellanemia,especiallypregnantwomen,haveincreased
requirementsforfolicacid.

Prescribing
Availableoverthecounter.

Doseanddoseinformation
Adult
Oralorparenteral:
1mg/d

Pediatric
Oralorparenteral:
0to6monthsofage:0.1mg/d
6to12monthsofage:0.25mg/d
1to2yearsofage:0.5mg/d
Overage2:1mg/d

Administration
Followintravenous,intramuscular,orsubcutaneousadministrationguidelines.

Contraindications
Hypersensitivitytofolicacidoranyothercomponent.

Cautions
HighdosesmaymaskhematologiceffectsofvitaminB12deficiencywhileallowing
neurologiccomplicationstoprogress,thereforeobscuringthediagnosisof

perniciousanemia
Donotadministeraloneforthetreatmentofperniciousanemiaandother
megaloblasticanemiasinpatientswithvitaminB12deficiency
Injectionmaycontainbenzoates,whichhavebeenassociatedwithneonatal
gaspingsyndrome.Usecautioninneonatesandpatientswhoaresensitiveto
benzoates

Adverseeffects
Rare:rash,bronchospasm,fever,sleepdisturbances,nausea,diarrhea,irritability.

Interactions
Phenobarbital(possiblyreducesserumphenobarbitallevels)
Phenytoin(possiblyreducesserumphenytoinlevels)
Primidone(possiblyreducesserumprimidonelevels)
Sulfasalazine(mayreduceabsorptionoffolicacid)

Pregnancyandlactation
Usedduringpregnancytopreventembryonicneuraltubedefects
Compatiblewithlactation

Pregnancycategory
PregnancycategoryA
PregnancycategoryC(ifusedindosesgreaterthantherecommendeddaily
allowance)

Othertherapies

Counselingandeducation
Parentsandcaregiversshouldbegiveneducationalinformationaboutsicklecell
diseaseattheearliestopportunity
Ifpossible,parentsshouldbegiveninformationandcounselingregardingthe
geneticsofsicklecelldiseaseduringpregnancy,includingtheavailabilityofcarrier
testingandprenataldiagnosis
Oncethediagnosishasbeenestablished,theimportanceofregularlyscheduled
healthmaintenancevisitspenicillinprophylaxisandimmunizations,including

pneumococcalvaccination,shouldbeemphasized
Informationshouldalsobegivenregardinghomemanagementofpain,importance
ofadequatehydration,andavoidanceofheatandcold
Parentsandcaregiversshouldbetaughttorecognizethesymptomsandsignsthat
requireurgentmedicalattention,includingenlargingspleenfeverpallorofthe
skin,lips,ornailbedsanyrespiratorysymptomsandpainorinabilitytomove
extremities.Instructioninabdominalpalpationforenlargedspleenandinformation
abouttheearlysignsofsplenicsequestration(eg,pallorandlistlessness)shouldbe
given
Caregiversshouldbetoldthattheearliestsymptomsinachildwithsicklecell
diseasewillmostlikelybepainfulswellingofthehandsand/orfeet(dactylitis)
Atalaterstage,informationshouldbegivenaboutcomplicationsaffectingolder
childrenandadults,suchasstroke,enuresis,priapism,cholelithiasis,delayed
puberty,proliferativeretinopathy,avascularnecrosisofthehiporshoulder,andleg
ulcers
Adolescentsshouldreceiveinformationaboutissuesrelatedtocontraception,
carriertestingofpartners,geneticcounseling,andprenataldiagnosis

Risks/benefits
Benefits:
Helptoenablethefamilytocopewiththeillness
Aidinoptimizingqualityoflife
Ensurethattheneedforacutecareisrecognizedasearlyaspossible
Enhancethechild'spotentialforasuccessfultransitiontoadulthood

Patientandcaregiverinformation
Familiesshouldbemadeawareofhowbesttoadjusttocaringforachildwitha
chronicillnessandgiveninformationonavailableresources,suchastheSickle
CellDiseaseAssociationofAmerica(http://www.sicklecelldisease.org)

Patientsshouldbemadeawareoffactorsthatmayprovokepainfulcrises,
includingextremesorchangesintemperature,infection,dehydration,high
altitude,stress,fatigue,andmenstruation
Intheearlymonthsofthechild'slife,emphasisshouldbeplacedonteaching
parentsandothercaregiverstorecognizeearlysignsofseriouscomplications

Geneticcounselingshouldbeprovided,withrecommendedtestingofparents,
siblings,andotherfamilymembers
Enrollmentwithacomprehensivesicklecellcenterisrecommended

Fluidreplacementtherapy
Inpatientswithmilddehydration,oralrehydrationsolutionshouldbegiven,
possiblywithsupplementalfluidsadministeredintravenously
Inpatientswithseveredehydration,treatmentisthesameasforshockisotonic
fluidbolusesmaybegivenfollowedbyfluidsatarateofatleast1.5timesthatfor
maintenancetherapy
Patientswithchronicsevereanemiaorpulmonaryhypertensionshouldbecarefully
monitoredduringfluidreplacementtherapytoensurethatcongestiveheartfailure
doesnotdevelop

Risks/benefits
Risk:
Potentialforcongestiveheartfailureinpatientswithchronicsevereanemia
carefulmonitoringisrequired
Benefits:
Correctshypertonicity
Compensatesforanyongoingfluidlossesimposedbyfever,hyposthenuria,
vomiting,ordiarrhea
Compensatesforincreasedurinarysodiumlossesduringcrises

Monitor
Carefulmonitoringisrequiredtoensurethatcongestiveheartfailuredoesnotdevelop.

Bloodtransfusions
Indicationsincludesymptomaticanemia,lifethreateningvasoocclusiveeventsor
acuteorgandysfunction,highriskprocedures(includinggeneralanesthesia),and
pregnancyinselectedcases
Duetotheriskofcomplications,transfusionshouldonlybeinitiatedafterserious
considerationoftheclinicalsettingandpossibleadverseeventshowever,blood
transfusionisoftencriticalfortreatingsicklecelldiseaseandmaybedoneona
regularbasisinsomepatients

Maybeusedeithertotreatspecificepisodes(episodictransfusion)oronanongoing
basis(chronictransfusion)
Episodictransfusions:
Usedtomanageacuteevents,suchasstroke,acutechestsyndrome,
widespreadinfection(sepsis),andorganfailure
Alsousedtomanagesevereanemiacausedbyspleniccrisisoraplastic
crisis
Donebeforemajorsurgery
Chronictransfusions:
Usedfortreatmentandpreventionofstrokerecommendedforchildren
athighriskforstroke
Maybeusedtoreducetheoccurrenceofpainfulcrisesinpatientswith
severe,protractedepisodes
Alsodoneinpatientswithpulmonaryhypertensionandchroniclung
disease,heartfailure,chronickidneyfailure,andseveresymptomatic
anemia
Simpleorexchangetransfusionsmaybedone
Simpletransfusions:
Usedformoderatelysevereanemiainpatientswithdyspneaorhypoxia
andinnonemergencysituationswhenthereisaneedforincreased
oxygen
Mayalsobeusedinitiallyforacutechestsyndrome
Exchangetransfusions:
Shouldbedonepromptlyinpatientswithacutecrisesandtoprevent
stroke
Mayalsobeusedtotreatsevereacutechestsyndromeandtoreducethe
riskofironoverloadinpatientsrequiringchronictransfusiontherapy
Useoferythrocytetransfusionfortheacutetreatmentofcerebrovasculareventsand
preventionoftheirrecurrenceinchildreniswellestablishedsuchtransfusionscan
bedoneregularlyaspartofachronictransfusionprogram(every45weeks)to
preventstroke
Patientswithsicklecelldiseasehavechronicanemia.Transfusingabovethe
baselinehematocritlevelcanleadtohyperviscosity,increasingtheriskofacute
thrombosis,jaundice,transfusionreactions,andhemosiderosis

Risks/benefits
Risks:
Overtransfusion(hyperviscosity,volumeoverload)
Transfusionreactions(acute,septic,febrile,andallergic)
Alloimmunizationtoerythrocyteantigens
Ironoverload,whichincreasestheriskofcomplications,includinglivercancer
andheartfailure,andmayrequirechelationtherapytoremoveexcessironstores
Transmissionofbloodbornediseases(hepatitisBandC,HIV,andother
microbiologicagents)
Benefits:
Suppresstheproductionofsicklederythrocytes
Maintaintherapeuticlevelsofnormalerythrocytes

Monitor
Liverbiopsy(orsuperconductingquantuminterferencedevice,ifavailable)to
assessforironoverload
Carefulmonitoringisrequiredforhyperviscosity.Monitorpatientforincreased
bloodpressure,changesinmentalstatus,andseizures
Monitorforimmunereactions,whichcanoccur5to20daysaftertransfusion
andcanresultinsevere,lifethreateninganemia

Patientandcaregiverinformation
Patientsshouldbeinformedoftherisksoftransfusion.

Evidence
Thereisevidencethataggressivetransfusionregimensarenomoreeffectivethanmore
conservativeregimensinreducingtheincidenceofperioperativecomplicationsin
patientswithsicklecelldisease.
Asystematicreviewassessingtherisksandbenefitsofpreoperativeblood
transfusioninpatientswithsicklecelldiseaseidentifiedonetrial,which
comparedanaggressivetransfusionregimen(aimedatdecreasingHbSto<30%
oftotalhemoglobin)withamoreconservativetransfusionregimen(aimedat
increasinghemoglobinto10g/dL).Thetworegimenswerefoundtobeequally

effectiveintermsofpreventingintraoperativeandpostoperativecomplications,
butthemoreconservativeregimenwasassociatedwithfewertransfusionrelated
adverseevents.However,thereviewersconcludedthatfurtherresearchisneeded
toidentifytheoptimaltransfusionregimenfordifferenttypesofsurgeryandto
addressthequestionofwhetherpreoperativetransfusionisneededinall
situations[12]LevelA
Thereisevidencethatlongtermbloodtransfusionregimenspreventstrokeinhigh
riskpatientswithsicklecelldisease,butthebenefitsmustbecarefullyweighedagainst
therisks.
Asystematicreviewassessingtherisksandbenefitsoflongtermblood
transfusionregimensforthepreventionofstrokeidentifiedonetrial,which
comparedalongtermbloodtransfusionregimen(aimedatmaintainingHbSat
<30%oftotalhemoglobin)withstandardcareinchildrenwithsicklecelldisease
whowerejudgedtobeathighriskforstrokeonthebasisoftranscranialDoppler
ultrasoundfindings.Significantlymorechildrenreceivingstandardcaresuffered
astrokecomparedwiththosereceivingbloodtransfusion,resultinginearly
terminationofthetrial.However,thereductionintherateofstrokewas
achievedattheexpenseofahighrateoftransfusionrelatedcomplications,
includingironoverload,alloimmunization,andtransfusionreactions.The
reviewersconcludedthatthedegreeofriskmustbebalancedagainsttheburden
ofalongtermtransfusionregimen,andtheynotethatfurtherresearchisneeded
toestablishtheidealcandidatesandregimenforthistreatmentmodality[13]
LevelA
AmulticenterRCTassignedchildrenwithinitiallyabnormaltranscranial
Dopplerultrasoundfindingswhohadreceivedchronicprophylacticblood
transfusionsfor30months,resultinginnormalizationoftranscranialDoppler
ultrasoundfindings,tocontinuedtransfusionornotransfusion.Thestudywas
terminatedearlywhen14patientsinthenotransfusiongroupdeveloped
abnormaltranscranialDopplerultrasoundfindings,and2patientssuffereda
stroke[14]LevelA

References
[12],[13],[14]

Bonemarrowtransplantation
Onlycurativetreatmentforsicklecelldisease
Usedinfrequentlyowingtothelackofasuitablebonemarrowdonor,highcost,and
associatedrisks

Involvestransplantationofhealthybonemarrow(allograft)fromasuitable
geneticallymatcheddonorinabonemarrowtransplantationunit
Maybeindicatedinchildren(butnotadults)withacutecomplicationsofsicklecell
disease,includingahistoryofstroke,recurrentacutechestsyndrome,sicklecell
associatedpulmonarydisease,andrecurrentvasoocclusivecrises
Thedecisiontoproceedwithtransplantationisdifficultgiventhe10%mortality
rate.Featuressuggestiveofseveredisease,includingearlydactylitis,elevated
leukocytecount,andearlystroke,canassistpatientsindecidingiftransplantationis
worththerisks
Forpatientswhochoosetoproceedwithtransplantation,thecriteriaforproceeding
varydependingonthetypeoftransplantandthetransplantcenter
Fullymatchedsiblingtransplantationwithstandardhighdoseinduction
chemotherapyisreservedforchildrenduetotheassociatedtoxicity
Matchedsiblingtransplantationusingalowintensitychemotherapeuticregimenis
beinginvestigatedforbothchildrenandadults
Standardhighdoseinductionchemotherapyiscontraindicatedinpatientswith
organdamage
Pretransplantationconsiderations:
Themajorityoftransplantshavetobefromdonatedbonemarrowthatgenetically
matchesthepatient'stissuetype,usuallytakenfromasibling
Immunosuppressiveagentsareoftengivenalongwiththepreparativeregimenin
theformofantithymocyteglobulin
Transplantationprocedure:
Theusualpreparativeregimenshaveinvolvedbusulfanandcyclophosphamide,
withmonitoringofbusulfanpharmacokinetics
Themajorityoftransplantshaveinvolvedunmanipulatedbonemarrowfrom
matchedsiblingdonors
Posttransplantationconsiderations:
Postoperativemonitoringisessentialforearlydetectionofgraftrejection,infection,
orothersurgicalcomplications
ThemajorityofpatientsaregivencyclosporinAaloneorincombinationwith

methylprednisoloneormethotrexateforposttransplantationgraftversushost
diseaseprophylaxis

Risks/benefits
Risks:
Increasedsusceptibilitytoinfection
Graftrejection
Diseaserecurrence
Possiblepulmonary,renal,gastrointestinal,cardiac,andneurologic
complications
Mortalityrateof10%
Shortandlongtermtoxicity
Benefit:
Canbecurative

Monitor
Postoperativemonitoringisessentialforearlydetectionofcomplicationssuchasgraft
rejectionandinfection.
Earlycomplications:
Graftversushostdisease:Thetransplantedhealthybonemarrowcellsmay
attackthepatient'scellsasthoughtheyareforeignorganisms.Drugsthat
suppresstheimmunesystemmustbeadministeredbeforetheprocedure,but
thismaynotbeeffectiveandalsodecreasesthebody'sabilitytofightinfections
Bleeding,pneumonia,andsevereinfection
Neurologiccomplications,includingstrokeandseizures
Transplantrelatedmortalityrateof7%to10%
Graftfailureratewithautologousrecoveryandreturntosicklecellanemiaof9%
Latecomplications:
Longtermcomplicationsmaybecausedbythedrugsusedintransplantation
andbythediseaseitself

Eveninpatientswhoexperiencesuccessfulcure,longtermconsequencesmay
includeahigherriskofcancer,infertility,prematuremenopause,anddelayed
growth

Evidence
Inacohortstudyof67patientswithsicklecelldiseasewhohadsufferedstrokeor
recurrentvasoocclusivecrisesandreceivedmyeloablativehematopoieticcell
transplantationfromHLAmatchedsiblings,64patientswerealiveatthetime
thestudyresultswerepublished,with5yearprobabilitiesofdiseasefree
survivalandoverallsurvivalof85%and97%,respectively.Graftfailureoccurred
in9patients,8ofwhomhadrecurrentcomplications[15]LevelB
Anothercohortstudyof51patientswithsicklecelldiseaseundergoing
transplantationofHLAmatchedhematopoieticstemcellsshowedthatoverall
survival,eventfreesurvival,anddiseasefreesurvivalratesat11yearswere88%,
76%,and80%,respectively,inpatientswhohadsufferedseriouscomplications
ofthediseaseand100%,93%,and93%,respectively,inpatientswhounderwent
transplantationearlier.Clinicalimprovementwasevidentinallpatientsinwhom
treatmentwassuccessful,althoughadverseeventsweremorecommoninthe
patientswhohadexperiencedcomplications[16]LevelB
Inacohortstudyof87consecutivepatientswithseveresicklecelldiseasewith
complications(mostwithevidenceofcerebralvasculopathy)receiving
hematopoieticstemcelltransplantationinFrance,theoverallsurvivaland
eventfreesurvivalrateswere93%and86%,respectively,atamedianfollowup
of6years.Graftversushostdiseasewasthemaincauseofprocedurerelated
deathbutdidnotoccurinpatientsreceivingcordblood[17]LevelB
Inasmallstudyof10adultsundergoingnonmyeloablativetransplantationof
CD34+peripheralbloodstemcellsfromHLAmatchedsiblingsaftertreatment
withtotalbodyirradiationplusalemtuzumab,all10patientswerealiveata
medianfollowupof30months.Ninepatientsexperiencedsuccessfulgrafting,
withnormalizationofhemoglobinandreversaloftheHbSphenotype.Side
effectsincludednarcoticwithdrawalsyndromeaswellaspneumonitisand
arthralgiafromsirolimusadministeredaftertransplantation[18]LevelC

References
[15],[16],[17],[18]

TENS
Electrodesattachedtoskinrelayelectricalimpulsesfromageneratortopainful
areas,interruptingthereceptionofpainmessagesbythebrain

Widelyusedasanalternativetopharmacologictreatmentsforchronicpain
Despitewidespreaduse,effectivenessremainscontroversial

Risks/benefits
Risks:
Donotuseinpatientswithpacemakersoroverareaswithmetalimplants
Prolongeduseofpadsonthesameareamaycauseskinirritation
Benefits:
Providespainrelief
Lowriskofsideeffects

Clinicalpearls
Infantsdiagnosedwithsicklecelldiseaseshouldreceivestandardwellchildcare,
immunizations,andprophylacticpenicillin,withmeticulousattentiontocounselingthe
parentorcaregiverregardingtakingtheinfant'stemperatureandbeingobservantforsigns
andsymptomsthatmightindicateanevolvingillness
Asthereisnoobjectivemeasuretodetermineifapatientwithsicklecelldiseaseishavinga
painfulcrisis,patientsmustbetakenattheirwordandgivenappropriatepainmedication

Never
Neverattempttotreatsevereornewsymptomsinapatientwithsicklecelldiseaseoverthe
telephone.Patientsmustbeseenandevaluated.

Managementinspecialcircumstances
Specialpatientgroups
Patientswithsicklecelldisease,especiallythosewithrecurrentsplenicsequestration,
mayhaveundergonesplenectomyandshouldbevaccinatedaccordinglywithinfluenza,
pneumococcal,andmeningococcalvaccines
Inaddition,manypatientscanbeconsideredtobefunctionallyasplenicbeginningin
earlychildhood,owingtorepetitivesicklingandsubsequentinfarctionswithinthespleen
Pregnancyposespotentiallyseriousproblemsforthemotherwithsicklecellanemiaand
fortheneonate:
Intheabsenceofmedicalsupervision,maternalandneonatalmortalityratesareas
highas20%and50%,respectively

Themostcommonproblemduringpregnancyisintrauterinegrowthretardation
Folicacidrequirementsareincreasedinpatientswithsicklecelldisease,and
adequatesupplementationiscrucialduringpregnancy

Patientsatisfaction/lifestylepriorities
Individualswithsicklecelldiseasehavebeenshowntohavealowerhealthrelatedquality
oflifethanthegeneralpopulation
Sicklecelldiseasecansignificantlyimpactanindividual'sabilitytoliveanormal,
productivelife
Itispossible,however,thatwithsocialsupportandclosemedicalfollowup,evenpatients
withseverediseasecancompleteschoolandachievetheirlifelonggoals
Interventionsthatmayimprovehealthrelatedqualityoflifeincludetheuseof
hydroxyureaandbonemarrowtransplantation

Patientandcaregiverissues
Impactoncareer,dependents,family,andfriends
Otherchildreninthefamilywhoarenotaffectedbythediseaseneedtohavetheirshare
ofattention,andtheyshouldbeinvolvedin,butnotoverwhelmedby,thecareofthechild
withsicklecelldisease
Geneticcounselingshouldbeprovided,withrecommendedtestingforparents,siblings,
andotherfamilymembers
Couplesmaywishtoavoidpregnancyifbothpartnersarecarriersforthesicklecelltrait

Questionsparentsask
WhenshouldIseekemergencycareformychild?Medicalcareshouldbesought
assoonasitappearsthatthechildishavinganacutecrisis.Sicklecelldiseasecannotbe
easilymanagedathome.Waitingtoolongtoseekmedicalcarecanhavesevere
consequences,asaseriousopportunisticinfectioncausingthecrisismaybemissed
Doesmychildneedtoseeapediatrichematologist,orcancarebeprovided
solelybyageneralpediatrician?Itisimportantthatchildrenwithsicklecelldisease
beseenbybothproviders.Apediatrichematologist,especiallyoneaffiliatedwitha
comprehensivesicklecellcenter,canoffertheadditionalsupportstaffthatmaybe
neededtohelpthechildcopewiththedisease

Healthseekingbehavior
Whathaveyoutakenforpainrelief?Onpresentation,aclearhistoryofmeasures

takentoalleviatepainshouldberecorded
Whatisthemainproblemtodaythatiscausingyoutobeinmorepainand
thatrequiresadjustmentofyourdosage?Physiciansneedtobeawareofthelong
termeffectsofescalatingdosesofnarcoticsandshouldscreenpatientsforevidenceof
acutediseasebeforeprescribinghigherdoses

Followup
Planforreview
Allpatientswithsicklecelldiseaseshouldberegisteredwithandmonitoredbya
specializedsicklecellclinic
Longtermmanagementandfollowupshouldbeindividualized,astherequirementsof
patientswithsicklecelldiseasevarygreatly
Itisimperativethatallpatientswithsicklecelldiseasereceiveroutinehealth
maintenance,includingappropriatevaccinations,suchasseasonalinfluenzaandH1N1
vaccinesandpneumococcalvaccine
Pulmonarycomplicationsarethemostcommoncauseofdeathinpatientswithsicklecell
disease,and,thus,screeningforpulmonaryhypertensionisessential
Renaldiseaseisalsoprevalentandcanbemissed,ascreatinineishypersecretedinurine.
Yearlyscreeningforproteinuriacanidentifyearlyrenaldisease
Patientsshouldhaveyearlyeyeexaminationswithfundoscopytoevaluateforretinopathy
Patientswithpriapismshouldbeevaluatedbyaurologistforlongtermmanagement
Patientsshouldalsoundergoroutinehealthscreeningsaswouldbedoneinthegeneral
population

Informationforpatientorcaregiver
Counselingandeducation(ZDD45DF8_32E_3CE)areessentialcomponentsinthe

managementofpatientswithsicklecelldisease.Thepatient'sfamilyshouldbemade
awareofhowbesttoadjusttocaringforsomeonewithachronicillness,including
informationonhomemanagementofpain,importanceofadequatehydration,avoidance
ofheatandcold,adherencetoroutineimmunizationregimens,andavailableresources(
eg,theSickleCellDiseaseAssociationofAmerica(http://www.sicklecelldisease.org))
Patientsshouldbemadeawareoffactorsthatmayprovokepainfulcrises,including
extremesorchangesintemperature,infection,dehydration,highaltitude,stress,fatigue,
andmenstruation

Intheearlymonthsofthechild'slife,emphasisshouldbeplacedonteachingparentsand
othercaregiverstorecognizeearlysignsofseriouscomplications
Geneticcounselingshouldbeprovided,withrecommendedtestingofparents,siblings,
andotherfamilymembers
Itisrecommendedthatpatientsenrollwithacomprehensivesicklecellcenter

Askforadvice
Question1
Arethereanyquickteststodetermineifapatienthassicklecelldisease?

Answer1
Sicklepreparationandhemoglobinsolubilitytestingareneithersensitivenorspecificfor
sicklecelldisease.Apositivehemoglobinsolubilitytestresultdoesnotdistinguishbetween
sicklecelltraitandsicklecelldisease.ThepresenceofHbFmayalsointerferewithsolubility
testing.Hemoglobinelectrophoresiswillaccuratelydefinethesicklecell
hemoglobinopathies.

Question2
Whatistherecommendationforscreeningforsicklecelldisease?

Answer2
Becauseitisnotpossibletoidentifyallpatientswithsicklecelldiseaseonthebasisof
epidemiologicdata(ethnicbackground,surname,appearance,orselfreport),universal
neonatalscreeningiscurrentlyrecommended.

Question3
Whatsignsandsymptomsindicatethatapatientwithsicklecelldiseasemaybedevelopinga
seriouscomplication?

Answer3
Weakness,severeheadache,orachangeinmentalorneurologicstatusmaysignala
stroke
Abdominalpain,pallor,andpossiblyshockmayindicatesplenicsequestration
Fevermaybeapresentingsignofsepsis
Painfulswellingofthehandsandfeetischaracteristicofdactylitis
Chestpain,shortnessofbreath,fever,andcoughmaypointtoacutechestsyndrome

Increasedpallorandfatiguemayindicateanaplasticcrisis

Question4
Whatmeasurescanbetakentopreventoratleastdelaythemorbidityandmortalityassociated
withsicklecelldisease?

Answer4
Enrollmentwithacomprehensivesicklecellcenterorprogramtoensureaccesstothe
newestdiagnosticandtherapeuticmodalities
Keepingimmunizationscurrent
Useofpenicillinprophylaxistoreducetheincidenceofinvasivepneumococcal
infection
Promptandthoroughevaluationofnewand/orincreasedsymptoms
Intervalscreeningproceduresandlaboratoryevaluations(eg,transcranialDoppler
ultrasound,ophthalmologicexamination)
Useofhydroxyureacandecreasemorbidity

Question5
Isthereanywaytoobjectivelyconfirm(ie,bywayoflaboratorystudies)thatapatientis
experiencingavasoocclusivecrisis?

Answer5
No,unfortunately,itisnotalwayspossibletodetermineifapatientishavingavaso
occlusivecrisisjustbyrelyingonchangesinvitalsignsorlaboratoryvalues(eg,decreased
hemoglobinlevelorincreasedreticulocytecount).Swellingandotherlocalchangesatthe
siteofpainarenotconsistentlypresent,either.Itisessentialtomaintainaclosepartnership
withthepatientaswellascontinuallyreassessingsymptomsandmodifyinginterventionsas
necessary.

Considerconsult
Urgentlyreferpatientswiththefollowingcomplicationsforinpatientmanagement:
Swollen,painfulbonesandjoints
CNSdeficit
Acutechestsyndromeorpneumonia
Mesentericsicklingandbowelischemia

Splenicorhepaticsequestration
Cholecystitis
Renalpapillarynecrosisresultingincolicorseverehematuria
Priapism
Hyphemaandretinaldetachment

Summaryofevidence
Evidence
Thereissomeevidencefortheeffectivenessofspecificanalgesicsoranalgesicregimensin
relievingthepainofavasoocclusivecrisis.
ThereissomeevidencefortheeffectivenessofparenteralketorolacfromRCTs,butthe
samplesizesweregenerallysmallsometrialshadconflictingresultsand,overall,the
evidenceisinsufficient[2],[3],[4],[5]LevelB
Oralcontrolledreleasemorphinehasbeenshowntobeaseffectiveasintravenousmorphine
inchildrenandadolescentsreceivinganinitialloadingdoseofintravenousmorphine[6]
LevelA
Thereissomeevidencefortheeffectivenessofprophylacticpenicillininpreventingpneumococcal
infectioninchildrenwithsicklecelldisease.
Asystematicreviewfoundthatprophylacticpenicillinsignificantlyreducedtheriskof
pneumococcalinfectionandwasassociatedwithminimaladversereactions[1]LevelA
Thereisevidencefortheeffectivenessofhydroxyureainthemanagementofpatientswithsickle
celldisease.
Systematicreviewshavefoundthattreatmentwithhydroxyurearesultsinfewerpainful
crises,bloodtransfusions,hospitaladmissions,andlifethreateningcomplications(acute
chestsyndromeinparticular)andincreasedtotalhemoglobinandHbFlevels[7],[8],[9]
LevelA
AnRCTshowedthattreatmentwithhydroxyurearesultedinareductioninpainfulcrises,
acutechestsyndrome,transfusionrequirements,andhospitaladmissionsandimproved
survivalatamedianfollowupof5to8years.BaselineHbFlevelsandpercentagechangein
serumlactatedehydrogenasebetweenbaselineand6monthspredictedsurvivalinpatients
receivinghydroxyurea[10]LevelA
Alongterm,observationalfollowupstudyofadultpatientswithsicklecellanemiawho

participatedinanRCToftheeffectsofhydroxyureaonvasoocclusiveeventsfrom1992to
1995foundthattheuseofhydroxyureaforfrequentpainfulcrisesappearedtoresultina
reducedmortalityrateafter9yearsoffollowup.SurvivalwasrelatedtoHbFlevelsandthe
frequencyofvasoocclusiveevents[11]LevelB
Thereissomeevidencefortheuseofbonemarrowtransplantationinpatientswithsicklecell
diseasewhoaresuitablecandidates.
Inacohortstudyof67patientswithsicklecelldiseasewhohadsufferedstrokeorrecurrent
vasoocclusivecrisesandreceivedmyeloablativehematopoieticcelltransplantationfrom
HLAmatchedsiblings,64patientswerealiveatthetimethestudyresultswerepublished,
with5yearprobabilitiesofdiseasefreesurvivalandoverallsurvivalof85%and97%,
respectively.Graftfailureoccurredin9patients,8ofwhomhadrecurrentcomplications[15]
LevelB
Anothercohortstudyof51patientswithsicklecelldiseaseundergoingtransplantationof
HLAmatchedhematopoieticstemcellsshowedthatoverallsurvival,eventfreesurvival,
anddiseasefreesurvivalratesat11yearswere88%,76%,and80%,respectively,inpatients
whohadsufferedseriouscomplicationsofthediseaseand100%,93%,and93%,
respectively,inpatientswhounderwenttransplantationearlier.Clinicalimprovementwas
evidentinallpatientsinwhomtreatmentwassuccessful,althoughadverseeventswere
morecommoninthepatientswhohadexperiencedcomplications[16]LevelB
Inacohortstudyof87consecutivepatientswithseveresicklecelldiseasewith
complications(mostwithevidenceofcerebralvasculopathy)receivinghematopoieticstem
celltransplantationinFrance,theoverallsurvivalandeventfreesurvivalrateswere93%
and86%,respectively,atamedianfollowupof6years.Graftversushostdiseasewasthe
maincauseofprocedurerelateddeathbutdidnotoccurinpatientsreceivingcordblood[17]
LevelB
Inasmallstudyof10adultsundergoingnonmyeloablativetransplantationofCD34+
peripheralbloodstemcellsfromHLAmatchedsiblingsaftertreatmentwithtotalbody
irradiationplusalemtuzumab,all10patientswerealiveatamedianfollowupof30months.
Ninepatientsexperiencedsuccessfulgrafting,withnormalizationofhemoglobinand
reversaloftheHbSphenotype.Sideeffectsincludednarcoticwithdrawalsyndromeaswell
aspneumonitisandarthralgiafromsirolimusadministeredaftertransplantation[18]LevelC
Thereissomeevidencefortheuseofbloodtransfusionsforsomeindicationsinpatientswith
sicklecelldisease.
Asystematicreviewfoundthatanaggressivepreoperativebloodtransfusionregimenisno
moreeffectivethanamoreconservativeregimenandthatamoreconservativeregimenis
associatedwithfewertransfusionrelatedadverseevents.However,furtherresearchis
neededtoidentifytheoptimalregimenfordifferenttypesofsurgeryandtoaddressthe

questionofwhetherpreoperativetransfusionisneededinallsituations[12]LevelA
Thereisevidencethatlongtermbloodtransfusionregimenspreventstrokeinhighrisk
patientswithsicklecelldisease,butthebenefitsmustbecarefullyweighedagainsttherisks
[13]LevelA

BasedonthefindingsofamulticenterRCTthatwasterminatedearly,itisnow
recommendedthatchildrenwithabnormaltranscranialDopplerultrasoundfindingsreceive
transfusiontherapyindefinitely[14]LevelA

References
[2],[3],[4],[5],[6],[1],[7],[8],[9],[10],[11],[15],[16],[17],[18],[12],[13],[14]

Outcomes
Prognosis
Chronicorgandamagesecondarytosicklecelldiseaseresultsinaplethoraofmedical
complications,althoughsomeprophylactictreatmentscanreducetheirincidence
Withoutbonemarrowtransplantation,whichistheonlypotentiallycurativetreatment,the
medianageatdeathis42yearsformenand48yearsforwomen

Factorsaffectingprognosis
HighlevelsofHbFhavebeenshowntohaveapositiveeffectonsurvivalnumberof
painfulepisodesandincidenceofproliferativeretinopathy,legulcers,andsplenic
sequestration
Ahighernumberofpainfulepisodesareseeninpatientswithhigherhematocritlevels
andlowerHbFlevels
Inheritanceofthalassemiaalongwithsicklecelldiseasehasbeenshowntobe
protectiveagainststroke,legulcers,cholelithiasis,andsplenicdysfunction
TranscranialDopplerultrasoundfindingsarethebestpredictorofthedevelopmentof
strokeinchildrenpatientswithvelocities200cm/sareatincreasedrisk
Theriskofpulmonaryhypertensionappearstobecorrelatedwiththedegreeof
hemolysisthus,patientswithhighbaselinelactatedehydrogenaselevelsandreticulocyte
countsappeartobemostatrisk
Increasedneutrophilcountsinpatientswithsicklecellanemiahavebeenassociatedwith
ahighermortalityrateandanincreasedriskofacutechestsyndromeandstroke

Clinicalpearls

Inadditiontopneumococcaldisease,patientswithsicklecelldiseaseareatriskfor
overwhelminginfectionwithotherencapsulatedorganisms,suchasHaemophilusand
Meningococcus
Attentiontothebowelregimenisnecessaryinpatientsreceivingopioidsforthe
treatmentofpainfulcrisesadministrationofastoolsoftenerisoftenrequired
Patientcontrolledanalgesiadevicesallowpatientstoexercisesomeautonomyovertheir
painmanagement

Progressionofdisease
Itisimperativethatallpatientswithsicklecelldiseasereceiveroutinehealth
maintenance
Pulmonarycomplicationsarethemostcommoncauseofdeathinthispatientpopulation
Screeningforearlyrenaldiseaseorthepresenceofpulmonaryhypertensioncanleadto
treatmentsthatmightpreventtheprogressionofthesedisorders
Patientsalsoneedroutinehealthscreenings,includingpapsmears,mammograms,and
colonoscopies,aswouldbedoneinthegeneralpopulation

Clinicalcomplications
Infection:owingtofunctionalasplenia,patientsaremoresusceptibletooverwhelming
sepsis
Acutesplenicsequestrationcrises:suddenenlargementofthespleenaccompaniedbya
decreaseinthehematocritlevelandanincreaseinthereticulocytecount
Aplasticcrises:cessationoferythrocyteproduction,oftenowingtohumanparvovirusB19
infection
Acutechestsyndrome:appearanceofanewpulmonaryinfiltrateonchestradiograph,fever,
andchestpain,whichcanbeassociatedwithanunderlyinginfection,hypoventilation,or
pulmonaryfatembolismthisisthemostcommoncauseofdeathinpatientswithsicklecell
disease
Stroke:occursin10%ofpatientsthemajorityofcasesinvolveinfarctsinthedistributionof
theinternalcarotidarteryorthemiddleoranteriorcerebralarteries
Gallbladderdisease:patientsarepronetothedevelopmentofpigmentedgallstones
Renalcomplications:patientsareunabletoconcentrateurineefficientlyandalsoareatrisk
forchronickidneydiseasebecausepatientswithsicklecelldiseasehyperexcretecreatinine,
itisapoormeasureofrenalfunction,androutinetestingformicroalbuminuriais

recommendedinstead

Considerconsult
Referpatients:
Inwhompulmonaryhypertensionissuspectedtoapulmonaryspecialistforathorough
evaluationandconsiderationoftherapy
Withproteinuriatoanephrologistforclosemonitoringofangiotensionconvertingenzyme
inhibitortherapy
Whodevelopavascularnecrosistoanorthopedicspecialistforsurgicalconsideration
Toanophthalmologistforyearlyeyeexaminationswithfundoscopytoevaluatefor
retinopathy
Withpriapismtoaurologistforevaluationforlongtermmanagement

Prevention
Geneticcounselingisofprimeimportanceinpreventingsicklecellanemia
Couplesplanningapregnancycangettestedforcarrierstatusatmedicalcentersandsicklecell
treatmentfacilities
Ageneticcounselorcanrefercouplesfortestinganddiscusstheriskstotheiroffspring
Couplesmaydecideagainsthavingchildrenifbothhavesicklecelltraitorotherknown
hemoglobinopathies(ie,aheterozygousHbSstate)

Screening
Ageneticcounselorshouldalwaysbeconsultedtoadviseandinformtheparents
Screeningofotherfamilymembersshouldalsobediscussedonceadiagnosishasbeen
established

Preconceptionscreening
Atriskcoupleswhoaretryingtoconceiveshouldbeofferedgeneticcounselingtodiscuss
availablecarrierdetectionmethodsandtheoptionofsubsequentprenataltesting,if
appropriate
EachparentshouldhavefullanalysisofbothHBBallelesbeforeprenataltestingisdone
intheeventthatoneparentisacarrierofanonHbSmutationthatpredisposestoa
differenthemoglobinopathy(eg,HbSCorHbSthalassemia)

MethodssuchasisoelectricfocusingandDNAbasedassaysmaybeusedinconjunction
withHPLCtodetectquantitativehemoglobinabnormalities,suchasthalassemias
Techniquesforpreimplantationdiagnostictestingmaybeavailableforfamiliesinwhich
thediseasecausingmutationshavebeenidentified

Prenatalscreening
DNAtesting(ZDCDCD36_4E_145)isavailableforprenataldiagnosisinatriskpregnancies

Samplesfortestingareusuallyobtainedbychorionicvillussamplingat8to10weeksof
gestationoramniocentesisat14to18weeksofgestation

Neonatalscreening
Currentguidelinesrecommenduniversalneonatalscreeningastheonlywaytoensure
thatallinfantswithsicklecelldiseasewillbeidentified.Screeninginfantsonlyfrom
specificracialorethnicgroupsisnotreliable
Routineneonatalscreeningforsicklecellanemiaisdoneinall50statesoftheU.S.,the
DistrictofColumbia,PuertoRico,andtheVirginIslands,allowingearlydiagnosisand
intervention(preventionofbacterialinfectioninparticular)
Hemoglobinstudies(130224):bloodsamplesareusuallyobtainedbyheelstick,anda

hemoglobinevaluationisdone,usuallywithin3daysofbirth
AbnormalresultscanbeconfirmedbyDNAanalysis

Resources
References
Evidencereferences
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disease.CochraneDatabaseSystRev.2002:CD003146
ViewInArticle(refInSitucid_19173)|CrossRef(http://dx.doi.org/10.1002%2F14651858.CD003146)

14.AdamsRJ,BrambillaDOptimizingPrimaryStrokePreventioninSickleCellAnemia
(STOP2)TrialInvestigators.Discontinuingprophylactictransfusionsusedtopreventstroke
insicklecelldisease.NEnglJMed.2005353:276978
ViewInArticle(refInSitucid_40345)|CrossRef(http://dx.doi.org/10.1056%2FNEJMoa050460)

15.PanepintoJA,WaltersMC,CarrerasJ,etal.Matchedrelateddonortransplantationfor
sicklecelldisease:reportfromtheCenterforInternationalBloodandTransplantResearch.
BrJHaematol.2007137:47985
ViewInArticle(refInSitucid_40373)|CrossRef(http://dx.doi.org/10.1111%2Fj.13652141.2007.06592.x)

16.VermylenC,CornuG,FersterA,etal.Haematopoieticstemcelltransplantationforsickle
cellanaemia:thefirst50patientstransplantedinBelgium.BoneMarrowTransplant.
199822:16
ViewInArticle(refInSitucid_40375)|CrossRef(http://dx.doi.org/10.1038%2Fsj.bmt.1701291)

17.BernaudinF,SocieG,KuentzM,etal.Longtermresultsofrelatedmyeloablativestemcell
transplantationtocuresicklecelldisease.Blood.2007110:274956
ViewInArticle(refInSitucid_40376)|CrossRef(http://dx.doi.org/10.1182%2Fblood200703079665)

18.HsiehMM,KangEM,FitzhughCD,etal.Allogeneichematopoieticstemcell
transplantationforsicklecelldisease.NEnglJMed.2009361:230917
ViewInArticle(refInSitucid_40342)|CrossRef(http://dx.doi.org/10.1056%2FNEJMoa0904971)

Guidelines
TheNationalHeart,Lung,andBloodInstitute(http://www.nhlbi.nih.gov/)hasproducedthefollowing:
TheManagementofSickleCellDisease
(http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf).NIHPublicationNo.022117.

Bethesda,MD:NationalHeart,Lung,andBloodInstitute2002
TheU.S.PreventiveServicesTaskForce(http://www.ahrq.gov/clinic/uspstfix.htm)hasproducedthe
following:
ScreeningforSickleCellDiseaseinNewborns:U.S.PreventiveServicesTaskForce
RecommendationStatement(http://www.ahrq.gov/clinic/uspstf07/sicklecell/sicklers.htm).AHRQ

PublicationNo.0705104EF2.Rockville,MD:AgencyforHealthcareResearchand
Quality2007
TheAmericanCollegeofObstetriciansandGynecologists(http://www.acog.org/)hasproducedthe
following:
ACOGCommitteeonObstetrics.ACOGPracticeBulletinNo.78:hemoglobinopathiesin
pregnancy.ObstetGynecol.2007109:22937.SummaryavailablefromtheNational
GuidelineClearinghouse(http://www.guideline.gov/summary/summary.aspx?doc_id=10920)

TheBritishSocietyforHaematology(http://www.bsh.org.uk/)hasproducedthefollowing:
ReesDC,OlujohungbeAD,ParkerNE,StephensAD,TelferP,WrightJBritish
CommitteeforStandardsinHaematologyGeneralHaematologyTaskForcebytheSickle
CellWorkingParty.Guidelinesforthemanagementoftheacutepainfulcrisisinsicklecell

disease(http://www.bcshguidelines.com/pdf/sicklecelldisease_0503.pdf).BrJHaematol.

2003120:74452
TheAmericanAcademyofFamilyPhysicians(http://www.aafp.org)haspublishedthefollowing:
WethersDL.Sicklecelldiseaseinchildhood.PartI.Laboratorydiagnosis,pathophysiologyand
healthmaintenance(http://www.aafp.org/afp/20000901/1013.html).AmFamPhysician.

200062:101320
WethersDL.Sicklecelldiseaseinchildhood:partII.Diagnosisandtreatmentofmajor
complicationsandrecentadvancesintreatment(http://www.aafp.org/afp/20000915/1309.html).Am

FamPhysician.200062:130914
YaleSH,NagibN,GuthrieT.Approachtothevasoocclusivecrisisinadultswithsicklecell
disease(http://www.aafp.org/afp/20000301/1349.html).AmFamPhysician.200061:134956

Furtherreading
DriscollMC.Sicklecelldisease.PediatrRev.200728:25968
FrenettePS,AtwehGF.Sicklecelldisease:olddiscoveries,newconcepts,andfuture
promise.JClinInvest.2007117:8508
MadaniG,PapadopoulouAM,HollowayB,etal.Theradiologicalmanifestationsofsickle
celldisease.ClinRadiol.200762:52838
SloanMA,AlexandrovAV,TegelerCH,etal.Assessment:transcranialDoppler
ultrasonography:reportoftheTherapeuticsandTechnologyAssessmentSubcommittee
oftheAmericanAcademyofNeurology.Neurology.200462:146881
ReddingLallingerR,KnollC.Sicklecelldiseasepathophysiologyandtreatment.Curr
ProblPediatrAdolescHealthCare.200636:34676
ClasterS,VichinskyEP.Managingsicklecelldisease.BMJ.2003327:11515
LottenbergR,HassellKL.Anevidencebasedapproachtothetreatmentofadultswith
sicklecelldisease.HematologyAmSocHematolEducProgram.2005:5865
ToddKH,GreenC,BonhamVL,etal.Sicklecelldiseaserelatedpain:crisisandconflict.J
Pain.20067:4538
BrawleyOW,CorneliusLJ,EdwardsLR,etal.NIHconsensusdevelopmentstatementon
hydroxyureatreatmentforsicklecelldisease.NIHConsensStateSciStatements.
200825:130
LiebeltEL,BalkSJ,FaberW,etal.NTPCERHRexpertpanelreportonthereproductive
anddevelopmentaltoxicityofhydroxyurea.BirthDefectsResBDevReprodToxicol.

200780:259366
KrishnamurtiL.Hematopoieticcelltransplantationforsicklecelldisease:stateoftheart.
ExpertOpinBiolTher20077:16172
JosephsonCD,SuLL,HillyerKL,HillyerCD.Transfusioninthepatientwithsicklecell
disease:acriticalreviewoftheliteratureandtransfusionguidelines.TransfusMedRev.
200721:11833
JohnsonCS.Arterialbloodpressureandhyperviscosityinsicklecelldisease.Hematol
OncolClinNorthAm.200519:82737,vi
KrishnamurtiL.Hematopoieticcelltransplantationforsicklecelldisease:stateoftheart.
ExpertOpinBiolTher.20077:16172
SadelainM.Recentadvancesinglobingenetransferforthetreatmentofthalassemia
andsicklecellanemia.CurrOpinHematol.200613:1428
SwitzerJA,HessDC,NicholsFT,AdamsRJ.Pathophysiologyandtreatmentofstrokein
sicklecelldisease:presentandfuture.LancetNeurol.20065:50112
WangWC.Thepathophysiology,prevention,andtreatmentofstrokeinsicklecell
disease.CurrOpinHematol.200714:1917
AbboudMR,AtwehGF.Preventionandmanagementofstrokesinpatientswithsickle
celldisease.CurrHematolRep.20065:1522
WangWC.Centralnervoussystemcomplicationsofsicklecelldiseaseinchildren:an
overview.ChildNeuropsychol200713:10319
GladwinMT,SachdevV,JisonML,etal.Pulmonaryhypertensionasariskfactorfor
deathinpatientswithsicklecelldisease.NEnglJMed.2004350:88695
MeltonCW,HaynesJ.Sickleacutelunginjury:roleofpreventionandearlyaggressive
interventionstrategiesonoutcome.ClinChestMed.200627:487502
MitchellBL.Sicklecelltraitandsuddendeathbringingithome.JNatlMedAssoc.
200799:3005
SteinbergMH.Predictingclinicalseverityinsicklecellanaemia.BrJHaematol
2005129:46581
MehtaSR,AfenyiAnnanA,ByrnsPJ,LottenbergR.Opportunitiestoimproveoutcomes
insicklecelldisease.AmFamPhysician.200674:30310

Associations

AmericanSickleCellAnemiaAssociation
10300CarnegieAvenue
Cleveland,OH44106
Tel:(216)2298600
Fax:(216)2294500
http://www.ascaa.org(http://www.ascaa.org)

SickleCellDiseaseAssociationofAmerica
231EastBaltimoreStreet,Suite800
Baltimore,MD21202
Tel:(410)5281555or(800)4218453TollFree
Fax:(410)5281495
Email:scdaa@sicklecelldisease.org
http://www.sicklecelldisease.org(http://www.sicklecelldisease.org)

Contributors
SophieLanzkron,MD
JenniferDomm,MD
KevinSweet,MS,CGC

Copyright2016Elsevier,Inc.Allrightsreserved.