CCJM delivers practical clinical articles relevant to internists, cardiologists, endocrinologists, and other specialists, all written by known experts.

Theme
medstat_ccjm
Top Sections
CME
Reviews
1-Minute Consult
The Clinical Picture
Smart Testing
Symptoms to Diagnosis
ccjm
Main menu
CCJM Main Menu
Explore menu
CCJM Explore Menu
Proclivity ID
18804001
Unpublish
Negative Keywords
gaming
gambling
compulsive behaviors
ammunition
assault rifle
black jack
Boko Haram
bondage
child abuse
cocaine
Daech
drug paraphernalia
explosion
gun
human trafficking
ISIL
ISIS
Islamic caliphate
Islamic state
mixed martial arts
MMA
molestation
national rifle association
NRA
nsfw
pedophile
pedophilia
poker
porn
pornography
psychedelic drug
recreational drug
sex slave rings
slot machine
terrorism
terrorist
Texas hold 'em
UFC
substance abuse
abuseed
abuseer
abusees
abuseing
abusely
abuses
aeolus
aeolused
aeoluser
aeoluses
aeolusing
aeolusly
aeoluss
ahole
aholeed
aholeer
aholees
aholeing
aholely
aholes
alcohol
alcoholed
alcoholer
alcoholes
alcoholing
alcoholly
alcohols
allman
allmaned
allmaner
allmanes
allmaning
allmanly
allmans
alted
altes
alting
altly
alts
analed
analer
anales
analing
anally
analprobe
analprobeed
analprobeer
analprobees
analprobeing
analprobely
analprobes
anals
anilingus
anilingused
anilinguser
anilinguses
anilingusing
anilingusly
anilinguss
anus
anused
anuser
anuses
anusing
anusly
anuss
areola
areolaed
areolaer
areolaes
areolaing
areolaly
areolas
areole
areoleed
areoleer
areolees
areoleing
areolely
areoles
arian
arianed
arianer
arianes
arianing
arianly
arians
aryan
aryaned
aryaner
aryanes
aryaning
aryanly
aryans
asiaed
asiaer
asiaes
asiaing
asialy
asias
ass
ass hole
ass lick
ass licked
ass licker
ass lickes
ass licking
ass lickly
ass licks
assbang
assbanged
assbangeded
assbangeder
assbangedes
assbangeding
assbangedly
assbangeds
assbanger
assbanges
assbanging
assbangly
assbangs
assbangsed
assbangser
assbangses
assbangsing
assbangsly
assbangss
assed
asser
asses
assesed
asseser
asseses
assesing
assesly
assess
assfuck
assfucked
assfucker
assfuckered
assfuckerer
assfuckeres
assfuckering
assfuckerly
assfuckers
assfuckes
assfucking
assfuckly
assfucks
asshat
asshated
asshater
asshates
asshating
asshatly
asshats
assholeed
assholeer
assholees
assholeing
assholely
assholes
assholesed
assholeser
assholeses
assholesing
assholesly
assholess
assing
assly
assmaster
assmastered
assmasterer
assmasteres
assmastering
assmasterly
assmasters
assmunch
assmunched
assmuncher
assmunches
assmunching
assmunchly
assmunchs
asss
asswipe
asswipeed
asswipeer
asswipees
asswipeing
asswipely
asswipes
asswipesed
asswipeser
asswipeses
asswipesing
asswipesly
asswipess
azz
azzed
azzer
azzes
azzing
azzly
azzs
babeed
babeer
babees
babeing
babely
babes
babesed
babeser
babeses
babesing
babesly
babess
ballsac
ballsaced
ballsacer
ballsaces
ballsacing
ballsack
ballsacked
ballsacker
ballsackes
ballsacking
ballsackly
ballsacks
ballsacly
ballsacs
ballsed
ballser
ballses
ballsing
ballsly
ballss
barf
barfed
barfer
barfes
barfing
barfly
barfs
bastard
bastarded
bastarder
bastardes
bastarding
bastardly
bastards
bastardsed
bastardser
bastardses
bastardsing
bastardsly
bastardss
bawdy
bawdyed
bawdyer
bawdyes
bawdying
bawdyly
bawdys
beaner
beanered
beanerer
beaneres
beanering
beanerly
beaners
beardedclam
beardedclamed
beardedclamer
beardedclames
beardedclaming
beardedclamly
beardedclams
beastiality
beastialityed
beastialityer
beastialityes
beastialitying
beastialityly
beastialitys
beatch
beatched
beatcher
beatches
beatching
beatchly
beatchs
beater
beatered
beaterer
beateres
beatering
beaterly
beaters
beered
beerer
beeres
beering
beerly
beeyotch
beeyotched
beeyotcher
beeyotches
beeyotching
beeyotchly
beeyotchs
beotch
beotched
beotcher
beotches
beotching
beotchly
beotchs
biatch
biatched
biatcher
biatches
biatching
biatchly
biatchs
big tits
big titsed
big titser
big titses
big titsing
big titsly
big titss
bigtits
bigtitsed
bigtitser
bigtitses
bigtitsing
bigtitsly
bigtitss
bimbo
bimboed
bimboer
bimboes
bimboing
bimboly
bimbos
bisexualed
bisexualer
bisexuales
bisexualing
bisexually
bisexuals
bitch
bitched
bitcheded
bitcheder
bitchedes
bitcheding
bitchedly
bitcheds
bitcher
bitches
bitchesed
bitcheser
bitcheses
bitchesing
bitchesly
bitchess
bitching
bitchly
bitchs
bitchy
bitchyed
bitchyer
bitchyes
bitchying
bitchyly
bitchys
bleached
bleacher
bleaches
bleaching
bleachly
bleachs
blow job
blow jobed
blow jober
blow jobes
blow jobing
blow jobly
blow jobs
blowed
blower
blowes
blowing
blowjob
blowjobed
blowjober
blowjobes
blowjobing
blowjobly
blowjobs
blowjobsed
blowjobser
blowjobses
blowjobsing
blowjobsly
blowjobss
blowly
blows
boink
boinked
boinker
boinkes
boinking
boinkly
boinks
bollock
bollocked
bollocker
bollockes
bollocking
bollockly
bollocks
bollocksed
bollockser
bollockses
bollocksing
bollocksly
bollockss
bollok
bolloked
bolloker
bollokes
bolloking
bollokly
bolloks
boner
bonered
bonerer
boneres
bonering
bonerly
boners
bonersed
bonerser
bonerses
bonersing
bonersly
bonerss
bong
bonged
bonger
bonges
bonging
bongly
bongs
boob
boobed
boober
boobes
boobies
boobiesed
boobieser
boobieses
boobiesing
boobiesly
boobiess
boobing
boobly
boobs
boobsed
boobser
boobses
boobsing
boobsly
boobss
booby
boobyed
boobyer
boobyes
boobying
boobyly
boobys
booger
boogered
boogerer
boogeres
boogering
boogerly
boogers
bookie
bookieed
bookieer
bookiees
bookieing
bookiely
bookies
bootee
booteeed
booteeer
booteees
booteeing
booteely
bootees
bootie
bootieed
bootieer
bootiees
bootieing
bootiely
booties
booty
bootyed
bootyer
bootyes
bootying
bootyly
bootys
boozeed
boozeer
boozees
boozeing
boozely
boozer
boozered
boozerer
boozeres
boozering
boozerly
boozers
boozes
boozy
boozyed
boozyer
boozyes
boozying
boozyly
boozys
bosomed
bosomer
bosomes
bosoming
bosomly
bosoms
bosomy
bosomyed
bosomyer
bosomyes
bosomying
bosomyly
bosomys
bugger
buggered
buggerer
buggeres
buggering
buggerly
buggers
bukkake
bukkakeed
bukkakeer
bukkakees
bukkakeing
bukkakely
bukkakes
bull shit
bull shited
bull shiter
bull shites
bull shiting
bull shitly
bull shits
bullshit
bullshited
bullshiter
bullshites
bullshiting
bullshitly
bullshits
bullshitsed
bullshitser
bullshitses
bullshitsing
bullshitsly
bullshitss
bullshitted
bullshitteded
bullshitteder
bullshittedes
bullshitteding
bullshittedly
bullshitteds
bullturds
bullturdsed
bullturdser
bullturdses
bullturdsing
bullturdsly
bullturdss
bung
bunged
bunger
bunges
bunging
bungly
bungs
busty
bustyed
bustyer
bustyes
bustying
bustyly
bustys
butt
butt fuck
butt fucked
butt fucker
butt fuckes
butt fucking
butt fuckly
butt fucks
butted
buttes
buttfuck
buttfucked
buttfucker
buttfuckered
buttfuckerer
buttfuckeres
buttfuckering
buttfuckerly
buttfuckers
buttfuckes
buttfucking
buttfuckly
buttfucks
butting
buttly
buttplug
buttpluged
buttpluger
buttpluges
buttpluging
buttplugly
buttplugs
butts
caca
cacaed
cacaer
cacaes
cacaing
cacaly
cacas
cahone
cahoneed
cahoneer
cahonees
cahoneing
cahonely
cahones
cameltoe
cameltoeed
cameltoeer
cameltoees
cameltoeing
cameltoely
cameltoes
carpetmuncher
carpetmunchered
carpetmuncherer
carpetmuncheres
carpetmunchering
carpetmuncherly
carpetmunchers
cawk
cawked
cawker
cawkes
cawking
cawkly
cawks
chinc
chinced
chincer
chinces
chincing
chincly
chincs
chincsed
chincser
chincses
chincsing
chincsly
chincss
chink
chinked
chinker
chinkes
chinking
chinkly
chinks
chode
chodeed
chodeer
chodees
chodeing
chodely
chodes
chodesed
chodeser
chodeses
chodesing
chodesly
chodess
clit
clited
cliter
clites
cliting
clitly
clitoris
clitorised
clitoriser
clitorises
clitorising
clitorisly
clitoriss
clitorus
clitorused
clitoruser
clitoruses
clitorusing
clitorusly
clitoruss
clits
clitsed
clitser
clitses
clitsing
clitsly
clitss
clitty
clittyed
clittyer
clittyes
clittying
clittyly
clittys
cocain
cocaine
cocained
cocaineed
cocaineer
cocainees
cocaineing
cocainely
cocainer
cocaines
cocaining
cocainly
cocains
cock
cock sucker
cock suckered
cock suckerer
cock suckeres
cock suckering
cock suckerly
cock suckers
cockblock
cockblocked
cockblocker
cockblockes
cockblocking
cockblockly
cockblocks
cocked
cocker
cockes
cockholster
cockholstered
cockholsterer
cockholsteres
cockholstering
cockholsterly
cockholsters
cocking
cockknocker
cockknockered
cockknockerer
cockknockeres
cockknockering
cockknockerly
cockknockers
cockly
cocks
cocksed
cockser
cockses
cocksing
cocksly
cocksmoker
cocksmokered
cocksmokerer
cocksmokeres
cocksmokering
cocksmokerly
cocksmokers
cockss
cocksucker
cocksuckered
cocksuckerer
cocksuckeres
cocksuckering
cocksuckerly
cocksuckers
coital
coitaled
coitaler
coitales
coitaling
coitally
coitals
commie
commieed
commieer
commiees
commieing
commiely
commies
condomed
condomer
condomes
condoming
condomly
condoms
coon
cooned
cooner
coones
cooning
coonly
coons
coonsed
coonser
coonses
coonsing
coonsly
coonss
corksucker
corksuckered
corksuckerer
corksuckeres
corksuckering
corksuckerly
corksuckers
cracked
crackwhore
crackwhoreed
crackwhoreer
crackwhorees
crackwhoreing
crackwhorely
crackwhores
crap
craped
craper
crapes
craping
craply
crappy
crappyed
crappyer
crappyes
crappying
crappyly
crappys
cum
cumed
cumer
cumes
cuming
cumly
cummin
cummined
cumminer
cummines
cumming
cumminged
cumminger
cumminges
cumminging
cummingly
cummings
cummining
cumminly
cummins
cums
cumshot
cumshoted
cumshoter
cumshotes
cumshoting
cumshotly
cumshots
cumshotsed
cumshotser
cumshotses
cumshotsing
cumshotsly
cumshotss
cumslut
cumsluted
cumsluter
cumslutes
cumsluting
cumslutly
cumsluts
cumstain
cumstained
cumstainer
cumstaines
cumstaining
cumstainly
cumstains
cunilingus
cunilingused
cunilinguser
cunilinguses
cunilingusing
cunilingusly
cunilinguss
cunnilingus
cunnilingused
cunnilinguser
cunnilinguses
cunnilingusing
cunnilingusly
cunnilinguss
cunny
cunnyed
cunnyer
cunnyes
cunnying
cunnyly
cunnys
cunt
cunted
cunter
cuntes
cuntface
cuntfaceed
cuntfaceer
cuntfacees
cuntfaceing
cuntfacely
cuntfaces
cunthunter
cunthuntered
cunthunterer
cunthunteres
cunthuntering
cunthunterly
cunthunters
cunting
cuntlick
cuntlicked
cuntlicker
cuntlickered
cuntlickerer
cuntlickeres
cuntlickering
cuntlickerly
cuntlickers
cuntlickes
cuntlicking
cuntlickly
cuntlicks
cuntly
cunts
cuntsed
cuntser
cuntses
cuntsing
cuntsly
cuntss
dago
dagoed
dagoer
dagoes
dagoing
dagoly
dagos
dagosed
dagoser
dagoses
dagosing
dagosly
dagoss
dammit
dammited
dammiter
dammites
dammiting
dammitly
dammits
damn
damned
damneded
damneder
damnedes
damneding
damnedly
damneds
damner
damnes
damning
damnit
damnited
damniter
damnites
damniting
damnitly
damnits
damnly
damns
dick
dickbag
dickbaged
dickbager
dickbages
dickbaging
dickbagly
dickbags
dickdipper
dickdippered
dickdipperer
dickdipperes
dickdippering
dickdipperly
dickdippers
dicked
dicker
dickes
dickface
dickfaceed
dickfaceer
dickfacees
dickfaceing
dickfacely
dickfaces
dickflipper
dickflippered
dickflipperer
dickflipperes
dickflippering
dickflipperly
dickflippers
dickhead
dickheaded
dickheader
dickheades
dickheading
dickheadly
dickheads
dickheadsed
dickheadser
dickheadses
dickheadsing
dickheadsly
dickheadss
dicking
dickish
dickished
dickisher
dickishes
dickishing
dickishly
dickishs
dickly
dickripper
dickrippered
dickripperer
dickripperes
dickrippering
dickripperly
dickrippers
dicks
dicksipper
dicksippered
dicksipperer
dicksipperes
dicksippering
dicksipperly
dicksippers
dickweed
dickweeded
dickweeder
dickweedes
dickweeding
dickweedly
dickweeds
dickwhipper
dickwhippered
dickwhipperer
dickwhipperes
dickwhippering
dickwhipperly
dickwhippers
dickzipper
dickzippered
dickzipperer
dickzipperes
dickzippering
dickzipperly
dickzippers
diddle
diddleed
diddleer
diddlees
diddleing
diddlely
diddles
dike
dikeed
dikeer
dikees
dikeing
dikely
dikes
dildo
dildoed
dildoer
dildoes
dildoing
dildoly
dildos
dildosed
dildoser
dildoses
dildosing
dildosly
dildoss
diligaf
diligafed
diligafer
diligafes
diligafing
diligafly
diligafs
dillweed
dillweeded
dillweeder
dillweedes
dillweeding
dillweedly
dillweeds
dimwit
dimwited
dimwiter
dimwites
dimwiting
dimwitly
dimwits
dingle
dingleed
dingleer
dinglees
dingleing
dinglely
dingles
dipship
dipshiped
dipshiper
dipshipes
dipshiping
dipshiply
dipships
dizzyed
dizzyer
dizzyes
dizzying
dizzyly
dizzys
doggiestyleed
doggiestyleer
doggiestylees
doggiestyleing
doggiestylely
doggiestyles
doggystyleed
doggystyleer
doggystylees
doggystyleing
doggystylely
doggystyles
dong
donged
donger
donges
donging
dongly
dongs
doofus
doofused
doofuser
doofuses
doofusing
doofusly
doofuss
doosh
dooshed
doosher
dooshes
dooshing
dooshly
dooshs
dopeyed
dopeyer
dopeyes
dopeying
dopeyly
dopeys
douchebag
douchebaged
douchebager
douchebages
douchebaging
douchebagly
douchebags
douchebagsed
douchebagser
douchebagses
douchebagsing
douchebagsly
douchebagss
doucheed
doucheer
douchees
doucheing
douchely
douches
douchey
doucheyed
doucheyer
doucheyes
doucheying
doucheyly
doucheys
drunk
drunked
drunker
drunkes
drunking
drunkly
drunks
dumass
dumassed
dumasser
dumasses
dumassing
dumassly
dumasss
dumbass
dumbassed
dumbasser
dumbasses
dumbassesed
dumbasseser
dumbasseses
dumbassesing
dumbassesly
dumbassess
dumbassing
dumbassly
dumbasss
dummy
dummyed
dummyer
dummyes
dummying
dummyly
dummys
dyke
dykeed
dykeer
dykees
dykeing
dykely
dykes
dykesed
dykeser
dykeses
dykesing
dykesly
dykess
erotic
eroticed
eroticer
erotices
eroticing
eroticly
erotics
extacy
extacyed
extacyer
extacyes
extacying
extacyly
extacys
extasy
extasyed
extasyer
extasyes
extasying
extasyly
extasys
fack
facked
facker
fackes
facking
fackly
facks
fag
faged
fager
fages
fagg
fagged
faggeded
faggeder
faggedes
faggeding
faggedly
faggeds
fagger
fagges
fagging
faggit
faggited
faggiter
faggites
faggiting
faggitly
faggits
faggly
faggot
faggoted
faggoter
faggotes
faggoting
faggotly
faggots
faggs
faging
fagly
fagot
fagoted
fagoter
fagotes
fagoting
fagotly
fagots
fags
fagsed
fagser
fagses
fagsing
fagsly
fagss
faig
faiged
faiger
faiges
faiging
faigly
faigs
faigt
faigted
faigter
faigtes
faigting
faigtly
faigts
fannybandit
fannybandited
fannybanditer
fannybandites
fannybanditing
fannybanditly
fannybandits
farted
farter
fartes
farting
fartknocker
fartknockered
fartknockerer
fartknockeres
fartknockering
fartknockerly
fartknockers
fartly
farts
felch
felched
felcher
felchered
felcherer
felcheres
felchering
felcherly
felchers
felches
felching
felchinged
felchinger
felchinges
felchinging
felchingly
felchings
felchly
felchs
fellate
fellateed
fellateer
fellatees
fellateing
fellately
fellates
fellatio
fellatioed
fellatioer
fellatioes
fellatioing
fellatioly
fellatios
feltch
feltched
feltcher
feltchered
feltcherer
feltcheres
feltchering
feltcherly
feltchers
feltches
feltching
feltchly
feltchs
feom
feomed
feomer
feomes
feoming
feomly
feoms
fisted
fisteded
fisteder
fistedes
fisteding
fistedly
fisteds
fisting
fistinged
fistinger
fistinges
fistinging
fistingly
fistings
fisty
fistyed
fistyer
fistyes
fistying
fistyly
fistys
floozy
floozyed
floozyer
floozyes
floozying
floozyly
floozys
foad
foaded
foader
foades
foading
foadly
foads
fondleed
fondleer
fondlees
fondleing
fondlely
fondles
foobar
foobared
foobarer
foobares
foobaring
foobarly
foobars
freex
freexed
freexer
freexes
freexing
freexly
freexs
frigg
frigga
friggaed
friggaer
friggaes
friggaing
friggaly
friggas
frigged
frigger
frigges
frigging
friggly
friggs
fubar
fubared
fubarer
fubares
fubaring
fubarly
fubars
fuck
fuckass
fuckassed
fuckasser
fuckasses
fuckassing
fuckassly
fuckasss
fucked
fuckeded
fuckeder
fuckedes
fuckeding
fuckedly
fuckeds
fucker
fuckered
fuckerer
fuckeres
fuckering
fuckerly
fuckers
fuckes
fuckface
fuckfaceed
fuckfaceer
fuckfacees
fuckfaceing
fuckfacely
fuckfaces
fuckin
fuckined
fuckiner
fuckines
fucking
fuckinged
fuckinger
fuckinges
fuckinging
fuckingly
fuckings
fuckining
fuckinly
fuckins
fuckly
fucknugget
fucknuggeted
fucknuggeter
fucknuggetes
fucknuggeting
fucknuggetly
fucknuggets
fucknut
fucknuted
fucknuter
fucknutes
fucknuting
fucknutly
fucknuts
fuckoff
fuckoffed
fuckoffer
fuckoffes
fuckoffing
fuckoffly
fuckoffs
fucks
fucksed
fuckser
fuckses
fucksing
fucksly
fuckss
fucktard
fucktarded
fucktarder
fucktardes
fucktarding
fucktardly
fucktards
fuckup
fuckuped
fuckuper
fuckupes
fuckuping
fuckuply
fuckups
fuckwad
fuckwaded
fuckwader
fuckwades
fuckwading
fuckwadly
fuckwads
fuckwit
fuckwited
fuckwiter
fuckwites
fuckwiting
fuckwitly
fuckwits
fudgepacker
fudgepackered
fudgepackerer
fudgepackeres
fudgepackering
fudgepackerly
fudgepackers
fuk
fuked
fuker
fukes
fuking
fukly
fuks
fvck
fvcked
fvcker
fvckes
fvcking
fvckly
fvcks
fxck
fxcked
fxcker
fxckes
fxcking
fxckly
fxcks
gae
gaeed
gaeer
gaees
gaeing
gaely
gaes
gai
gaied
gaier
gaies
gaiing
gaily
gais
ganja
ganjaed
ganjaer
ganjaes
ganjaing
ganjaly
ganjas
gayed
gayer
gayes
gaying
gayly
gays
gaysed
gayser
gayses
gaysing
gaysly
gayss
gey
geyed
geyer
geyes
geying
geyly
geys
gfc
gfced
gfcer
gfces
gfcing
gfcly
gfcs
gfy
gfyed
gfyer
gfyes
gfying
gfyly
gfys
ghay
ghayed
ghayer
ghayes
ghaying
ghayly
ghays
ghey
gheyed
gheyer
gheyes
gheying
gheyly
gheys
gigolo
gigoloed
gigoloer
gigoloes
gigoloing
gigololy
gigolos
goatse
goatseed
goatseer
goatsees
goatseing
goatsely
goatses
godamn
godamned
godamner
godamnes
godamning
godamnit
godamnited
godamniter
godamnites
godamniting
godamnitly
godamnits
godamnly
godamns
goddam
goddamed
goddamer
goddames
goddaming
goddamly
goddammit
goddammited
goddammiter
goddammites
goddammiting
goddammitly
goddammits
goddamn
goddamned
goddamner
goddamnes
goddamning
goddamnly
goddamns
goddams
goldenshower
goldenshowered
goldenshowerer
goldenshoweres
goldenshowering
goldenshowerly
goldenshowers
gonad
gonaded
gonader
gonades
gonading
gonadly
gonads
gonadsed
gonadser
gonadses
gonadsing
gonadsly
gonadss
gook
gooked
gooker
gookes
gooking
gookly
gooks
gooksed
gookser
gookses
gooksing
gooksly
gookss
gringo
gringoed
gringoer
gringoes
gringoing
gringoly
gringos
gspot
gspoted
gspoter
gspotes
gspoting
gspotly
gspots
gtfo
gtfoed
gtfoer
gtfoes
gtfoing
gtfoly
gtfos
guido
guidoed
guidoer
guidoes
guidoing
guidoly
guidos
handjob
handjobed
handjober
handjobes
handjobing
handjobly
handjobs
hard on
hard oned
hard oner
hard ones
hard oning
hard only
hard ons
hardknight
hardknighted
hardknighter
hardknightes
hardknighting
hardknightly
hardknights
hebe
hebeed
hebeer
hebees
hebeing
hebely
hebes
heeb
heebed
heeber
heebes
heebing
heebly
heebs
hell
helled
heller
helles
helling
hellly
hells
hemp
hemped
hemper
hempes
hemping
hemply
hemps
heroined
heroiner
heroines
heroining
heroinly
heroins
herp
herped
herper
herpes
herpesed
herpeser
herpeses
herpesing
herpesly
herpess
herping
herply
herps
herpy
herpyed
herpyer
herpyes
herpying
herpyly
herpys
hitler
hitlered
hitlerer
hitleres
hitlering
hitlerly
hitlers
hived
hiver
hives
hiving
hivly
hivs
hobag
hobaged
hobager
hobages
hobaging
hobagly
hobags
homey
homeyed
homeyer
homeyes
homeying
homeyly
homeys
homo
homoed
homoer
homoes
homoey
homoeyed
homoeyer
homoeyes
homoeying
homoeyly
homoeys
homoing
homoly
homos
honky
honkyed
honkyer
honkyes
honkying
honkyly
honkys
hooch
hooched
hoocher
hooches
hooching
hoochly
hoochs
hookah
hookahed
hookaher
hookahes
hookahing
hookahly
hookahs
hooker
hookered
hookerer
hookeres
hookering
hookerly
hookers
hoor
hoored
hoorer
hoores
hooring
hoorly
hoors
hootch
hootched
hootcher
hootches
hootching
hootchly
hootchs
hooter
hootered
hooterer
hooteres
hootering
hooterly
hooters
hootersed
hooterser
hooterses
hootersing
hootersly
hooterss
horny
hornyed
hornyer
hornyes
hornying
hornyly
hornys
houstoned
houstoner
houstones
houstoning
houstonly
houstons
hump
humped
humpeded
humpeder
humpedes
humpeding
humpedly
humpeds
humper
humpes
humping
humpinged
humpinger
humpinges
humpinging
humpingly
humpings
humply
humps
husbanded
husbander
husbandes
husbanding
husbandly
husbands
hussy
hussyed
hussyer
hussyes
hussying
hussyly
hussys
hymened
hymener
hymenes
hymening
hymenly
hymens
inbred
inbreded
inbreder
inbredes
inbreding
inbredly
inbreds
incest
incested
incester
incestes
incesting
incestly
incests
injun
injuned
injuner
injunes
injuning
injunly
injuns
jackass
jackassed
jackasser
jackasses
jackassing
jackassly
jackasss
jackhole
jackholeed
jackholeer
jackholees
jackholeing
jackholely
jackholes
jackoff
jackoffed
jackoffer
jackoffes
jackoffing
jackoffly
jackoffs
jap
japed
japer
japes
japing
japly
japs
japsed
japser
japses
japsing
japsly
japss
jerkoff
jerkoffed
jerkoffer
jerkoffes
jerkoffing
jerkoffly
jerkoffs
jerks
jism
jismed
jismer
jismes
jisming
jismly
jisms
jiz
jized
jizer
jizes
jizing
jizly
jizm
jizmed
jizmer
jizmes
jizming
jizmly
jizms
jizs
jizz
jizzed
jizzeded
jizzeder
jizzedes
jizzeding
jizzedly
jizzeds
jizzer
jizzes
jizzing
jizzly
jizzs
junkie
junkieed
junkieer
junkiees
junkieing
junkiely
junkies
junky
junkyed
junkyer
junkyes
junkying
junkyly
junkys
kike
kikeed
kikeer
kikees
kikeing
kikely
kikes
kikesed
kikeser
kikeses
kikesing
kikesly
kikess
killed
killer
killes
killing
killly
kills
kinky
kinkyed
kinkyer
kinkyes
kinkying
kinkyly
kinkys
kkk
kkked
kkker
kkkes
kkking
kkkly
kkks
klan
klaned
klaner
klanes
klaning
klanly
klans
knobend
knobended
knobender
knobendes
knobending
knobendly
knobends
kooch
kooched
koocher
kooches
koochesed
koocheser
koocheses
koochesing
koochesly
koochess
kooching
koochly
koochs
kootch
kootched
kootcher
kootches
kootching
kootchly
kootchs
kraut
krauted
krauter
krautes
krauting
krautly
krauts
kyke
kykeed
kykeer
kykees
kykeing
kykely
kykes
lech
leched
lecher
leches
leching
lechly
lechs
leper
lepered
leperer
leperes
lepering
leperly
lepers
lesbiansed
lesbianser
lesbianses
lesbiansing
lesbiansly
lesbianss
lesbo
lesboed
lesboer
lesboes
lesboing
lesboly
lesbos
lesbosed
lesboser
lesboses
lesbosing
lesbosly
lesboss
lez
lezbianed
lezbianer
lezbianes
lezbianing
lezbianly
lezbians
lezbiansed
lezbianser
lezbianses
lezbiansing
lezbiansly
lezbianss
lezbo
lezboed
lezboer
lezboes
lezboing
lezboly
lezbos
lezbosed
lezboser
lezboses
lezbosing
lezbosly
lezboss
lezed
lezer
lezes
lezing
lezly
lezs
lezzie
lezzieed
lezzieer
lezziees
lezzieing
lezziely
lezzies
lezziesed
lezzieser
lezzieses
lezziesing
lezziesly
lezziess
lezzy
lezzyed
lezzyer
lezzyes
lezzying
lezzyly
lezzys
lmaoed
lmaoer
lmaoes
lmaoing
lmaoly
lmaos
lmfao
lmfaoed
lmfaoer
lmfaoes
lmfaoing
lmfaoly
lmfaos
loined
loiner
loines
loining
loinly
loins
loinsed
loinser
loinses
loinsing
loinsly
loinss
lubeed
lubeer
lubees
lubeing
lubely
lubes
lusty
lustyed
lustyer
lustyes
lustying
lustyly
lustys
massa
massaed
massaer
massaes
massaing
massaly
massas
masterbate
masterbateed
masterbateer
masterbatees
masterbateing
masterbately
masterbates
masterbating
masterbatinged
masterbatinger
masterbatinges
masterbatinging
masterbatingly
masterbatings
masterbation
masterbationed
masterbationer
masterbationes
masterbationing
masterbationly
masterbations
masturbate
masturbateed
masturbateer
masturbatees
masturbateing
masturbately
masturbates
masturbating
masturbatinged
masturbatinger
masturbatinges
masturbatinging
masturbatingly
masturbatings
masturbation
masturbationed
masturbationer
masturbationes
masturbationing
masturbationly
masturbations
methed
mether
methes
mething
methly
meths
militaryed
militaryer
militaryes
militarying
militaryly
militarys
mofo
mofoed
mofoer
mofoes
mofoing
mofoly
mofos
molest
molested
molester
molestes
molesting
molestly
molests
moolie
moolieed
moolieer
mooliees
moolieing
mooliely
moolies
moron
moroned
moroner
morones
moroning
moronly
morons
motherfucka
motherfuckaed
motherfuckaer
motherfuckaes
motherfuckaing
motherfuckaly
motherfuckas
motherfucker
motherfuckered
motherfuckerer
motherfuckeres
motherfuckering
motherfuckerly
motherfuckers
motherfucking
motherfuckinged
motherfuckinger
motherfuckinges
motherfuckinging
motherfuckingly
motherfuckings
mtherfucker
mtherfuckered
mtherfuckerer
mtherfuckeres
mtherfuckering
mtherfuckerly
mtherfuckers
mthrfucker
mthrfuckered
mthrfuckerer
mthrfuckeres
mthrfuckering
mthrfuckerly
mthrfuckers
mthrfucking
mthrfuckinged
mthrfuckinger
mthrfuckinges
mthrfuckinging
mthrfuckingly
mthrfuckings
muff
muffdiver
muffdivered
muffdiverer
muffdiveres
muffdivering
muffdiverly
muffdivers
muffed
muffer
muffes
muffing
muffly
muffs
murdered
murderer
murderes
murdering
murderly
murders
muthafuckaz
muthafuckazed
muthafuckazer
muthafuckazes
muthafuckazing
muthafuckazly
muthafuckazs
muthafucker
muthafuckered
muthafuckerer
muthafuckeres
muthafuckering
muthafuckerly
muthafuckers
mutherfucker
mutherfuckered
mutherfuckerer
mutherfuckeres
mutherfuckering
mutherfuckerly
mutherfuckers
mutherfucking
mutherfuckinged
mutherfuckinger
mutherfuckinges
mutherfuckinging
mutherfuckingly
mutherfuckings
muthrfucking
muthrfuckinged
muthrfuckinger
muthrfuckinges
muthrfuckinging
muthrfuckingly
muthrfuckings
nad
naded
nader
nades
nading
nadly
nads
nadsed
nadser
nadses
nadsing
nadsly
nadss
nakeded
nakeder
nakedes
nakeding
nakedly
nakeds
napalm
napalmed
napalmer
napalmes
napalming
napalmly
napalms
nappy
nappyed
nappyer
nappyes
nappying
nappyly
nappys
nazi
nazied
nazier
nazies
naziing
nazily
nazis
nazism
nazismed
nazismer
nazismes
nazisming
nazismly
nazisms
negro
negroed
negroer
negroes
negroing
negroly
negros
nigga
niggaed
niggaer
niggaes
niggah
niggahed
niggaher
niggahes
niggahing
niggahly
niggahs
niggaing
niggaly
niggas
niggased
niggaser
niggases
niggasing
niggasly
niggass
niggaz
niggazed
niggazer
niggazes
niggazing
niggazly
niggazs
nigger
niggered
niggerer
niggeres
niggering
niggerly
niggers
niggersed
niggerser
niggerses
niggersing
niggersly
niggerss
niggle
niggleed
niggleer
nigglees
niggleing
nigglely
niggles
niglet
nigleted
nigleter
nigletes
nigleting
nigletly
niglets
nimrod
nimroded
nimroder
nimrodes
nimroding
nimrodly
nimrods
ninny
ninnyed
ninnyer
ninnyes
ninnying
ninnyly
ninnys
nooky
nookyed
nookyer
nookyes
nookying
nookyly
nookys
nuccitelli
nuccitellied
nuccitellier
nuccitellies
nuccitelliing
nuccitellily
nuccitellis
nympho
nymphoed
nymphoer
nymphoes
nymphoing
nympholy
nymphos
opium
opiumed
opiumer
opiumes
opiuming
opiumly
opiums
orgies
orgiesed
orgieser
orgieses
orgiesing
orgiesly
orgiess
orgy
orgyed
orgyer
orgyes
orgying
orgyly
orgys
paddy
paddyed
paddyer
paddyes
paddying
paddyly
paddys
paki
pakied
pakier
pakies
pakiing
pakily
pakis
pantie
pantieed
pantieer
pantiees
pantieing
pantiely
panties
pantiesed
pantieser
pantieses
pantiesing
pantiesly
pantiess
panty
pantyed
pantyer
pantyes
pantying
pantyly
pantys
pastie
pastieed
pastieer
pastiees
pastieing
pastiely
pasties
pasty
pastyed
pastyer
pastyes
pastying
pastyly
pastys
pecker
peckered
peckerer
peckeres
peckering
peckerly
peckers
pedo
pedoed
pedoer
pedoes
pedoing
pedoly
pedophile
pedophileed
pedophileer
pedophilees
pedophileing
pedophilely
pedophiles
pedophilia
pedophiliac
pedophiliaced
pedophiliacer
pedophiliaces
pedophiliacing
pedophiliacly
pedophiliacs
pedophiliaed
pedophiliaer
pedophiliaes
pedophiliaing
pedophilialy
pedophilias
pedos
penial
penialed
penialer
peniales
penialing
penially
penials
penile
penileed
penileer
penilees
penileing
penilely
peniles
penis
penised
peniser
penises
penising
penisly
peniss
perversion
perversioned
perversioner
perversiones
perversioning
perversionly
perversions
peyote
peyoteed
peyoteer
peyotees
peyoteing
peyotely
peyotes
phuck
phucked
phucker
phuckes
phucking
phuckly
phucks
pillowbiter
pillowbitered
pillowbiterer
pillowbiteres
pillowbitering
pillowbiterly
pillowbiters
pimp
pimped
pimper
pimpes
pimping
pimply
pimps
pinko
pinkoed
pinkoer
pinkoes
pinkoing
pinkoly
pinkos
pissed
pisseded
pisseder
pissedes
pisseding
pissedly
pisseds
pisser
pisses
pissing
pissly
pissoff
pissoffed
pissoffer
pissoffes
pissoffing
pissoffly
pissoffs
pisss
polack
polacked
polacker
polackes
polacking
polackly
polacks
pollock
pollocked
pollocker
pollockes
pollocking
pollockly
pollocks
poon
pooned
pooner
poones
pooning
poonly
poons
poontang
poontanged
poontanger
poontanges
poontanging
poontangly
poontangs
porn
porned
porner
pornes
porning
pornly
porno
pornoed
pornoer
pornoes
pornography
pornographyed
pornographyer
pornographyes
pornographying
pornographyly
pornographys
pornoing
pornoly
pornos
porns
prick
pricked
pricker
prickes
pricking
prickly
pricks
prig
priged
priger
priges
priging
prigly
prigs
prostitute
prostituteed
prostituteer
prostitutees
prostituteing
prostitutely
prostitutes
prude
prudeed
prudeer
prudees
prudeing
prudely
prudes
punkass
punkassed
punkasser
punkasses
punkassing
punkassly
punkasss
punky
punkyed
punkyer
punkyes
punkying
punkyly
punkys
puss
pussed
pusser
pusses
pussies
pussiesed
pussieser
pussieses
pussiesing
pussiesly
pussiess
pussing
pussly
pusss
pussy
pussyed
pussyer
pussyes
pussying
pussyly
pussypounder
pussypoundered
pussypounderer
pussypounderes
pussypoundering
pussypounderly
pussypounders
pussys
puto
putoed
putoer
putoes
putoing
putoly
putos
queaf
queafed
queafer
queafes
queafing
queafly
queafs
queef
queefed
queefer
queefes
queefing
queefly
queefs
queer
queered
queerer
queeres
queering
queerly
queero
queeroed
queeroer
queeroes
queeroing
queeroly
queeros
queers
queersed
queerser
queerses
queersing
queersly
queerss
quicky
quickyed
quickyer
quickyes
quickying
quickyly
quickys
quim
quimed
quimer
quimes
quiming
quimly
quims
racy
racyed
racyer
racyes
racying
racyly
racys
rape
raped
rapeded
rapeder
rapedes
rapeding
rapedly
rapeds
rapeed
rapeer
rapees
rapeing
rapely
raper
rapered
raperer
raperes
rapering
raperly
rapers
rapes
rapist
rapisted
rapister
rapistes
rapisting
rapistly
rapists
raunch
raunched
rauncher
raunches
raunching
raunchly
raunchs
rectus
rectused
rectuser
rectuses
rectusing
rectusly
rectuss
reefer
reefered
reeferer
reeferes
reefering
reeferly
reefers
reetard
reetarded
reetarder
reetardes
reetarding
reetardly
reetards
reich
reiched
reicher
reiches
reiching
reichly
reichs
retard
retarded
retardeded
retardeder
retardedes
retardeding
retardedly
retardeds
retarder
retardes
retarding
retardly
retards
rimjob
rimjobed
rimjober
rimjobes
rimjobing
rimjobly
rimjobs
ritard
ritarded
ritarder
ritardes
ritarding
ritardly
ritards
rtard
rtarded
rtarder
rtardes
rtarding
rtardly
rtards
rum
rumed
rumer
rumes
ruming
rumly
rump
rumped
rumper
rumpes
rumping
rumply
rumprammer
rumprammered
rumprammerer
rumprammeres
rumprammering
rumprammerly
rumprammers
rumps
rums
ruski
ruskied
ruskier
ruskies
ruskiing
ruskily
ruskis
sadism
sadismed
sadismer
sadismes
sadisming
sadismly
sadisms
sadist
sadisted
sadister
sadistes
sadisting
sadistly
sadists
scag
scaged
scager
scages
scaging
scagly
scags
scantily
scantilyed
scantilyer
scantilyes
scantilying
scantilyly
scantilys
schlong
schlonged
schlonger
schlonges
schlonging
schlongly
schlongs
scrog
scroged
scroger
scroges
scroging
scrogly
scrogs
scrot
scrote
scroted
scroteed
scroteer
scrotees
scroteing
scrotely
scroter
scrotes
scroting
scrotly
scrots
scrotum
scrotumed
scrotumer
scrotumes
scrotuming
scrotumly
scrotums
scrud
scruded
scruder
scrudes
scruding
scrudly
scruds
scum
scumed
scumer
scumes
scuming
scumly
scums
seaman
seamaned
seamaner
seamanes
seamaning
seamanly
seamans
seamen
seamened
seamener
seamenes
seamening
seamenly
seamens
seduceed
seduceer
seducees
seduceing
seducely
seduces
semen
semened
semener
semenes
semening
semenly
semens
shamedame
shamedameed
shamedameer
shamedamees
shamedameing
shamedamely
shamedames
shit
shite
shiteater
shiteatered
shiteaterer
shiteateres
shiteatering
shiteaterly
shiteaters
shited
shiteed
shiteer
shitees
shiteing
shitely
shiter
shites
shitface
shitfaceed
shitfaceer
shitfacees
shitfaceing
shitfacely
shitfaces
shithead
shitheaded
shitheader
shitheades
shitheading
shitheadly
shitheads
shithole
shitholeed
shitholeer
shitholees
shitholeing
shitholely
shitholes
shithouse
shithouseed
shithouseer
shithousees
shithouseing
shithousely
shithouses
shiting
shitly
shits
shitsed
shitser
shitses
shitsing
shitsly
shitss
shitt
shitted
shitteded
shitteder
shittedes
shitteding
shittedly
shitteds
shitter
shittered
shitterer
shitteres
shittering
shitterly
shitters
shittes
shitting
shittly
shitts
shitty
shittyed
shittyer
shittyes
shittying
shittyly
shittys
shiz
shized
shizer
shizes
shizing
shizly
shizs
shooted
shooter
shootes
shooting
shootly
shoots
sissy
sissyed
sissyer
sissyes
sissying
sissyly
sissys
skag
skaged
skager
skages
skaging
skagly
skags
skank
skanked
skanker
skankes
skanking
skankly
skanks
slave
slaveed
slaveer
slavees
slaveing
slavely
slaves
sleaze
sleazeed
sleazeer
sleazees
sleazeing
sleazely
sleazes
sleazy
sleazyed
sleazyer
sleazyes
sleazying
sleazyly
sleazys
slut
slutdumper
slutdumpered
slutdumperer
slutdumperes
slutdumpering
slutdumperly
slutdumpers
sluted
sluter
slutes
sluting
slutkiss
slutkissed
slutkisser
slutkisses
slutkissing
slutkissly
slutkisss
slutly
sluts
slutsed
slutser
slutses
slutsing
slutsly
slutss
smegma
smegmaed
smegmaer
smegmaes
smegmaing
smegmaly
smegmas
smut
smuted
smuter
smutes
smuting
smutly
smuts
smutty
smuttyed
smuttyer
smuttyes
smuttying
smuttyly
smuttys
snatch
snatched
snatcher
snatches
snatching
snatchly
snatchs
sniper
snipered
sniperer
sniperes
snipering
sniperly
snipers
snort
snorted
snorter
snortes
snorting
snortly
snorts
snuff
snuffed
snuffer
snuffes
snuffing
snuffly
snuffs
sodom
sodomed
sodomer
sodomes
sodoming
sodomly
sodoms
spic
spiced
spicer
spices
spicing
spick
spicked
spicker
spickes
spicking
spickly
spicks
spicly
spics
spik
spoof
spoofed
spoofer
spoofes
spoofing
spoofly
spoofs
spooge
spoogeed
spoogeer
spoogees
spoogeing
spoogely
spooges
spunk
spunked
spunker
spunkes
spunking
spunkly
spunks
steamyed
steamyer
steamyes
steamying
steamyly
steamys
stfu
stfued
stfuer
stfues
stfuing
stfuly
stfus
stiffy
stiffyed
stiffyer
stiffyes
stiffying
stiffyly
stiffys
stoneded
stoneder
stonedes
stoneding
stonedly
stoneds
stupided
stupider
stupides
stupiding
stupidly
stupids
suckeded
suckeder
suckedes
suckeding
suckedly
suckeds
sucker
suckes
sucking
suckinged
suckinger
suckinges
suckinging
suckingly
suckings
suckly
sucks
sumofabiatch
sumofabiatched
sumofabiatcher
sumofabiatches
sumofabiatching
sumofabiatchly
sumofabiatchs
tard
tarded
tarder
tardes
tarding
tardly
tards
tawdry
tawdryed
tawdryer
tawdryes
tawdrying
tawdryly
tawdrys
teabagging
teabagginged
teabagginger
teabagginges
teabagginging
teabaggingly
teabaggings
terd
terded
terder
terdes
terding
terdly
terds
teste
testee
testeed
testeeed
testeeer
testeees
testeeing
testeely
testeer
testees
testeing
testely
testes
testesed
testeser
testeses
testesing
testesly
testess
testicle
testicleed
testicleer
testiclees
testicleing
testiclely
testicles
testis
testised
testiser
testises
testising
testisly
testiss
thrusted
thruster
thrustes
thrusting
thrustly
thrusts
thug
thuged
thuger
thuges
thuging
thugly
thugs
tinkle
tinkleed
tinkleer
tinklees
tinkleing
tinklely
tinkles
tit
tited
titer
tites
titfuck
titfucked
titfucker
titfuckes
titfucking
titfuckly
titfucks
titi
titied
titier
tities
titiing
titily
titing
titis
titly
tits
titsed
titser
titses
titsing
titsly
titss
tittiefucker
tittiefuckered
tittiefuckerer
tittiefuckeres
tittiefuckering
tittiefuckerly
tittiefuckers
titties
tittiesed
tittieser
tittieses
tittiesing
tittiesly
tittiess
titty
tittyed
tittyer
tittyes
tittyfuck
tittyfucked
tittyfucker
tittyfuckered
tittyfuckerer
tittyfuckeres
tittyfuckering
tittyfuckerly
tittyfuckers
tittyfuckes
tittyfucking
tittyfuckly
tittyfucks
tittying
tittyly
tittys
toke
tokeed
tokeer
tokees
tokeing
tokely
tokes
toots
tootsed
tootser
tootses
tootsing
tootsly
tootss
tramp
tramped
tramper
trampes
tramping
tramply
tramps
transsexualed
transsexualer
transsexuales
transsexualing
transsexually
transsexuals
trashy
trashyed
trashyer
trashyes
trashying
trashyly
trashys
tubgirl
tubgirled
tubgirler
tubgirles
tubgirling
tubgirlly
tubgirls
turd
turded
turder
turdes
turding
turdly
turds
tush
tushed
tusher
tushes
tushing
tushly
tushs
twat
twated
twater
twates
twating
twatly
twats
twatsed
twatser
twatses
twatsing
twatsly
twatss
undies
undiesed
undieser
undieses
undiesing
undiesly
undiess
unweded
unweder
unwedes
unweding
unwedly
unweds
uzi
uzied
uzier
uzies
uziing
uzily
uzis
vag
vaged
vager
vages
vaging
vagly
vags
valium
valiumed
valiumer
valiumes
valiuming
valiumly
valiums
venous
virgined
virginer
virgines
virgining
virginly
virgins
vixen
vixened
vixener
vixenes
vixening
vixenly
vixens
vodkaed
vodkaer
vodkaes
vodkaing
vodkaly
vodkas
voyeur
voyeured
voyeurer
voyeures
voyeuring
voyeurly
voyeurs
vulgar
vulgared
vulgarer
vulgares
vulgaring
vulgarly
vulgars
wang
wanged
wanger
wanges
wanging
wangly
wangs
wank
wanked
wanker
wankered
wankerer
wankeres
wankering
wankerly
wankers
wankes
wanking
wankly
wanks
wazoo
wazooed
wazooer
wazooes
wazooing
wazooly
wazoos
wedgie
wedgieed
wedgieer
wedgiees
wedgieing
wedgiely
wedgies
weeded
weeder
weedes
weeding
weedly
weeds
weenie
weenieed
weenieer
weeniees
weenieing
weeniely
weenies
weewee
weeweeed
weeweeer
weeweees
weeweeing
weeweely
weewees
weiner
weinered
weinerer
weineres
weinering
weinerly
weiners
weirdo
weirdoed
weirdoer
weirdoes
weirdoing
weirdoly
weirdos
wench
wenched
wencher
wenches
wenching
wenchly
wenchs
wetback
wetbacked
wetbacker
wetbackes
wetbacking
wetbackly
wetbacks
whitey
whiteyed
whiteyer
whiteyes
whiteying
whiteyly
whiteys
whiz
whized
whizer
whizes
whizing
whizly
whizs
whoralicious
whoralicioused
whoraliciouser
whoraliciouses
whoraliciousing
whoraliciously
whoraliciouss
whore
whorealicious
whorealicioused
whorealiciouser
whorealiciouses
whorealiciousing
whorealiciously
whorealiciouss
whored
whoreded
whoreder
whoredes
whoreding
whoredly
whoreds
whoreed
whoreer
whorees
whoreface
whorefaceed
whorefaceer
whorefacees
whorefaceing
whorefacely
whorefaces
whorehopper
whorehoppered
whorehopperer
whorehopperes
whorehoppering
whorehopperly
whorehoppers
whorehouse
whorehouseed
whorehouseer
whorehousees
whorehouseing
whorehousely
whorehouses
whoreing
whorely
whores
whoresed
whoreser
whoreses
whoresing
whoresly
whoress
whoring
whoringed
whoringer
whoringes
whoringing
whoringly
whorings
wigger
wiggered
wiggerer
wiggeres
wiggering
wiggerly
wiggers
woody
woodyed
woodyer
woodyes
woodying
woodyly
woodys
wop
woped
woper
wopes
woping
woply
wops
wtf
wtfed
wtfer
wtfes
wtfing
wtfly
wtfs
xxx
xxxed
xxxer
xxxes
xxxing
xxxly
xxxs
yeasty
yeastyed
yeastyer
yeastyes
yeastying
yeastyly
yeastys
yobbo
yobboed
yobboer
yobboes
yobboing
yobboly
yobbos
zoophile
zoophileed
zoophileer
zoophilees
zoophileing
zoophilely
zoophiles
anal
ass
ass lick
balls
ballsac
bisexual
bleach
causas
cheap
cost of miracles
cunt
display network stats
fart
fda and death
fda AND warn
fda AND warning
fda AND warns
feom
fuck
gfc
humira AND expensive
illegal
madvocate
masturbation
nuccitelli
overdose
porn
shit
snort
texarkana
direct\-acting antivirals
assistance
ombitasvir
support path
harvoni
abbvie
direct-acting antivirals
paritaprevir
advocacy
ledipasvir
vpak
ritonavir with dasabuvir
program
gilead
greedy
financial
needy
fake-ovir
viekira pak
v pak
sofosbuvir
support
oasis
discount
dasabuvir
protest
ritonavir
Negative Keywords Excluded Elements
header[@id='header']
section[contains(@class, 'nav-hidden')]
footer[@id='footer']
div[contains(@class, 'pane-pub-article-cleveland-clinic')]
div[contains(@class, 'pane-pub-home-cleveland-clinic')]
div[contains(@class, 'pane-pub-topic-cleveland-clinic')]
div[contains(@class, 'panel-panel-inner')]
div[contains(@class, 'pane-node-field-article-topics')]
section[contains(@class, 'footer-nav-section-wrapper')]
Altmetric
DSM Affiliated
Display in offset block
Disqus Exclude
Best Practices
CE/CME
Education Center
Medical Education Library
Enable Disqus
Display Author and Disclosure Link
Publication Type
Society
Slot System
Featured Buckets
Disable Sticky Ads
Disable Ad Block Mitigation
Featured Buckets Admin
LayerRx MD-IQ Id
773
Show Ads on this Publication's Homepage
Consolidated Pub
Show Article Page Numbers on TOC
Use larger logo size
Off
publication_blueconic_enabled
Off
Show More Destinations Menu
Disable Adhesion on Publication
Off
Restore Menu Label on Mobile Navigation
Disable Facebook Pixel from Publication
Exclude this publication from publication selection on articles and quiz

What are the caveats to using sodium phosphate agents for bowel preparation?

Article Type
Changed
Tue, 04/17/2018 - 11:04
Display Headline
What are the caveats to using sodium phosphate agents for bowel preparation?

Sodium phosphate (NaP) agents were introduced to provide a gentler alternative to polyethylene glycol (PEG) bowel preparations, which require patients to drink up to 4 liters of fluid over a few hours.

However, in May 2006 the US Food and Drug Administration (FDA) issued an alert that NaP products for bowel cleansing may, in some patients, pose a risk of acute phosphate nephropathy, a rare form of acute renal failure.

Although NaP preparations are generally safe and well tolerated, they can cause significant fluid shifts and electrolyte abnormalities. As such, they should not be used in patients with baseline electrolyte imbalances, renal or hepatic dysfunction, or a number of other comorbidities.

CURRENT BOWEL-CLEANSING OPTIONS

For many years the standard preparation for bowel cleansing was a 4-liter or a 2-liter PEG electrolyte solution plus a laxative (eg, magnesium citrate, bisacodyl, or senna).1–3 The most frequent complaint heard from patients was that “the preparation is worse than the colonoscopy,” attributable to the taste and volume of the fluid they had to consume. Thus, compliance was often a significant issue with patients presenting for colonoscopy. In fact, inadequate bowel preparation is one of the most common reasons polyps are missed during colonoscopy.

Aqueous and tablet forms of NaP (sometimes with a laxative) have become a widely used alternative to PEG solutions because they require much less volume and as a result are more palatable, thereby improving compliance.4,5

NaP agents cleanse the colon by osmotically drawing plasma water into the bowel lumen. The patient must drink significant amounts of water or other oral solutions to prevent dehydration.

NaP-based bowel-cleansing agents are available in two forms: aqueous solution and tablet. Aqueous NaP (such as Fleet Phospho-soda) is a low-volume hyperosmotic solution containing 48 g of monobasic NaP and 18 g of dibasic NaP per 100 mL.6 An oral tablet form (such as Visicol and OsmoPrep) was developed to improve patient tolerance.7 Each 2-g tablet of Visicol contains 1,500 mg of active ingredients (monobasic and dibasic NaP) and 460 mg of microcrystalline cellulose, an inert polymer. Each OsmoPrep tablet contains 1,500 mg of the same active ingredients as Visicol, but the inert ingredients include PEG and magnesium stearate.

At first, the regimen was 40 tablets such as Visicol to be taken with water and bisacodyl. Subsequent regimens such as OsmoPrep with fewer tablets have been shown to be as effective and better tolerated.8 Microcrystalline cellulose in the tablet can produce a residue that may obscure the bowel mucosa. Newer preparations contain lower amounts of this inert ingredient, allowing for improved visualization of the colonic mucosa during colonoscopy.9

ADVANTAGES OF SODIUM PHOSPHATE BOWEL CLEANSERS

In a recent review article, Burke and Church10 noted that NaP cleansing regimens have been shown to be superior to PEG-electrolyte lavage solution with respect to tolerability and acceptance by patients, improved quality of bowel preparation, better mucosal visualization, and more efficient endoscopic examination. In addition, the volume of the preparation may also help decrease the risk of aspiration in some patients.2,3

DISADVANTAGES OF SODIUM PHOSPHATE AGENTS

Despite their comparable or better efficacy and their better tolerability, NaP agents have certain disadvantages.

Effects on the colonic mucosa

In rare cases NaP agents have been shown to alter the microscopic and macroscopic features of the colonic mucosa, and they can induce aphthoid erosions that may mimic those seen in inflammatory bowel disease and enteropathy or colopathy associated with nonsteroidal anti-inflammatory drugs (NSAIDs).11–13 Therefore, NaP agents should not be used prior to the initial endoscopic evaluation of patients with suspected inflammatory bowel disease, microscopic colitis, or NSAID-induced colonopathy.

Fluid and electrolyte shifts

Because NaP acts by drawing plasma water into the bowel lumen, significant volume and electrolyte shifts may occur.14,15 These can cause hypokalemia, hyperphosphatemia, hypocalcemia, hyponatremia or hypernatremia, hypomagnesemia, elevated blood urea nitrogen levels, decreased exercise capacity, increased plasma osmolarity,15–17 seizures,18 and acute renal failure with or without nephrocalcinosis.17,19–21

Thus, patients with significant comorbidities—such as a recent history of myocardial infarction, renal or hepatic insufficiency, or malnutrition—should not use NaP agents.22

Pivotal study of adverse events

In May 2006, the FDA issued an alert outlining the concerns of using oral NaP in specific patient populations. Of note were documented cases of acute phosphate nephropathy in 21 patients who used aqueous NaP (Fleet Phospho-Soda or Fleet Accu-Prep), and in 1 patient who used NaP tablets (Visicol).23 Acute renal injury was not limited to patients with preexisting renal insufficiency. It is uncertain whether this means that otherwise healthy people suffered renal injury or had risk factors besides renal insufficiency, since the data cited by the FDA report do not elucidate the possible risk factors for the development of nephropathy in patients with no preexisting renal insufficiency. So far, no cases of acute phosphate nephropathy or acute renal failure have been reported with OsmoPrep, a NaP tablet bowel preparation recently approved by the FDA.24 The long-term safety of OsmoPrep needs further evaluation.

 

 

PROCEED WITH CAUTION

Certain situations such as advanced age and cardiac, renal, and hepatic dysfunction call for extreme caution in the use of NaP bowel preparation agents. Therefore, it is recommended that patients with the following conditions should avoid using NaP agents for colon preparation:

  • Hepatic or renal insufficiency (there are no data as to the degree of hepatic or renal insufficiency)
  • Congestive heart failure
  • Over age 65
  • Dehydration or hypercalcemia
  • Chronic use of drugs that affect renal perfusion, such as NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or diuretics for hypertension.

Patients who take diuretics should not take them while they are using NaP for bowel preparation because of the risk of electrolyte abnormalities such as hypokalemia. In patients who have no alternative but to proceed with NaP preparation, our recommendation would be that the patient hold off taking diuretics, ACE inhibitors, and angiotensin receptor blockers while using the NaP prep. Given the importance of these medications in controlling diseases such as hypertension, the physician and the patient should jointly determine whether the benefits of using an NaP agent justify holding these drugs. We believe that patients taking these drugs should try using a PEG solution before considering NaP.

TASK FORCE GUIDELINES

Guidelines for using NaP bowel preparation agents, published by a task force of the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Society of American Gastrointestinal and Endoscopic Surgeons,25 include the following caveats:

  • Aqueous and tablet NaP colonic preparations are an alternative to PEG solutions, except in pediatric populations, patients over age 65, and those with bowel obstruction or other structural intestinal disorder, gut dysmotility, renal or hepatic insufficiency, congestive heart failure, or seizure disorder.
  • Dosing should be 45 mL in divided doses, 10 to 12 hours apart, with at least one dose taken on the morning of the procedure.25
  • The significant volume contraction and resulting dehydration seen in some patients using NaP preparations may be lessened by encouraging patients to drink fluids liberally during the days leading up to their procedure, and especially during NaP bowel preparation.26
  • NaP tablets should be dosed as 32 to 40 tablets. On the evening before the procedure the patient should take 20 tablets and then 12 to 20 tablets approximately 3 to 5 hours before undergoing endoscopy. The tablets should be taken four at a time every 15 minutes with approximately 8 oz of clear liquid.25

To maximize the efficacy and safety of colonoscopy, it is paramount that the colon be adequately prepared. Agents for bowel cleansing should be inexpensive, effective, safe, palatable, and easy to take. The most commonly used regimens are based on either PEG or NaP, and each has advantages and disadvantages (Table 1). The decision whether to use PEG or NaP for bowel cleansing should be individualized and should take into consideration the pros and cons of the agents and the patient’s general health.

References
  1. Sharma VK, Chockalingham SK, Ugheoke EA, et al. Prospective, randomized, controlled comparison of the use of polyethylene glycol electrolyte lavage solution in four-liter versus two-liter volumes and pretreatment with either magnesium citrate or bisacodyl for colonoscopy preparation. Gastrointest Endosc 1998; 47:167171.
  2. Frommer D. Cleansing ability and tolerance of three bowel preparations for colonoscopy. Dis Colon Rectum 1997; 40:100104.
  3. Hsu CW, Imperiale TF. Meta-analysis and cost comparison of polyethylene glycol lavage versus sodium phosphate for colonoscopy preparation. Gastrointest Endosc 1998; 48:276282.
  4. Poon CM, Lee DWH, Mak SK, et al. Two liters of polyethylene glycol-electrolyte solution versus sodium phosphate as bowel cleansing regimen for colonoscopy: a prospective randomized controlled trial. Endoscopy 2002; 34:560563.
  5. Afridi SA, Barthel JS, King PD, et al. Prospective, randomized trial comparing a new sodium phosphate-bisacodyl regimen with conventional PEG-ES lavage for outpatient colonoscopy preparation. Gastrointest Endosc 1995; 41:485489.
  6. Schiller LR. Clinical pharmacology and use of laxatives and lavage solutions. J Clin Gastroenterol 1988; 28:1118.
  7. Kastenberg D, Chasen R, Choudhary C, et al. Efficacy and safety of sodium phosphate tablets compared with PEG solution in colon cleansing. Two identically designed, randomized, controlled, parallel group multicenter phase III trials. Gastrointest Endosc 2001; 54:705713.
  8. Rex DK, Chasen R, Pushpin MB. Safety and efficacy of two reduced dosing regimens of sodium phosphate tablets for preparation prior to colonoscopy. Aliment Pharmacol Ther 2002; 16:937944.
  9. Rex DK, Khashab M. Efficacy and tolerability of a new formulation of sodium phosphate tablets and a reduced sodium phosphate dose, in colon cleansing: a single-center open-label pilot trial. Aliment Pharmacol Ther 2005; 21:465468.
  10. Burke CA, Church JM. Enhancing the quality of colonoscopy: the importance of bowel purgatives. Gastrointest Endosc 2007; 66:565573.
  11. Rejchrt S, Bures J, Siroky M, et al. A prospective, observational study of colonic mucosal abnormalities associated with orally administered sodium phosphate for colon cleansing before colonoscopy. Gastrointest Endosc 2004; 59:651654.
  12. Hixson LJ. Colorectal ulcers associated with sodium phosphate catharsis. Gastrointest Endosc 1995; 42:101102.
  13. Zwas FR, Cirillo NW, El-Serag HB, Eisen RN. Colonic mucosal abnormalities associated with oral sodium phosphate solution. Gastrointest Endosc 1996; 43:463466.
  14. Clarkston WK, Tsen TN, Dies DF, Schratz CL, Vaswani SK, Bjerregaard P. Oral sodium phosphate versus sulfate-free polyethylene glycol electrolyte lavage solution in outpatient preparation for colonoscopy: a prospective comparison. Gastrointest Endosc 1996; 43:4248.
  15. Kolts BE, Lyles WE, Achem SR, et al. A comparison of the effectiveness and patient tolerance of oral sodium phosphate, castor oil, and standard electrolyte lavage for colonoscopy or sigmoidoscopy preparations. Am J Gastroenterol 1993; 88:12181223.
  16. Holte K, Neilsen KG, Madsen JL, Kehlet H. Physiologic effects of bowel preparation. Dis Colon Rectum 2004; 47:13971402.
  17. Clarkston WK, Tsen TN, Dies DF, et al. Oral sodium phosphate versus sulfate-free polyethylene glycol electrolyte lavage solution in outpatient preparation for colonoscopy: a prospective comparison. Gastrointest Endosc 1996; 43:4248.
  18. Frizelle FA, Colls BM. Hyponatremia and seizures after bowel preparation: report of three cases. Dis Colon Rectum 2005; 48:393396.
  19. Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004; 35:675684.
  20. Lieberman DA, Ghormley J, Flora K. Effect of oral sodium phosphate colon preparation on serum electrolytes in patients with normal serum creatinine. Gastrointest Endosc 1996; 43:467469.
  21. Gremse DA, Sacks AI, Raines S. Comparison of oral sodium phosphate to polyethylene-glycol-based solution for bowel preparation in children. J Pediatric Gastroenterol Nutr 1996; 23:586590.
  22. Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colonic cleanser. Drugs 2004; 64:16971714.
  23. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005; 16:33893396.
  24. FDA Alert. Patient information sheet. Oral sodium phosphate (OSP) products for bowel cleansing. 2006 May, Accessed January 8, 2008. www.fda.gov/CDER/drug/InfoSheets/patient/OSP_solutionPIS.htm.
  25. Wexner SD, Beck DE, Baron TH, et al. A consensus document on bowel preparation before colonoscopy prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Gastrointest Endosc 2006; 63:894909.
  26. Huynh T, Vanner S, Paterson W. Safety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia. Am J Gastroenterol 1995; 90:104107.
Article PDF
Author and Disclosure Information

Rohit Makkar, MD
Department of General Internal Medicine, Cleveland Clinic

Bo Shen, MD
Department of Gastroenterology and Hepatology, Cleveland Clinic

Address: Bo Shen, MD, Department of Gastroenterology and Hepatology, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Issue
Cleveland Clinic Journal of Medicine - 75(3)
Publications
Topics
Page Number
173-176
Sections
Author and Disclosure Information

Rohit Makkar, MD
Department of General Internal Medicine, Cleveland Clinic

Bo Shen, MD
Department of Gastroenterology and Hepatology, Cleveland Clinic

Address: Bo Shen, MD, Department of Gastroenterology and Hepatology, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Author and Disclosure Information

Rohit Makkar, MD
Department of General Internal Medicine, Cleveland Clinic

Bo Shen, MD
Department of Gastroenterology and Hepatology, Cleveland Clinic

Address: Bo Shen, MD, Department of Gastroenterology and Hepatology, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Article PDF
Article PDF

Sodium phosphate (NaP) agents were introduced to provide a gentler alternative to polyethylene glycol (PEG) bowel preparations, which require patients to drink up to 4 liters of fluid over a few hours.

However, in May 2006 the US Food and Drug Administration (FDA) issued an alert that NaP products for bowel cleansing may, in some patients, pose a risk of acute phosphate nephropathy, a rare form of acute renal failure.

Although NaP preparations are generally safe and well tolerated, they can cause significant fluid shifts and electrolyte abnormalities. As such, they should not be used in patients with baseline electrolyte imbalances, renal or hepatic dysfunction, or a number of other comorbidities.

CURRENT BOWEL-CLEANSING OPTIONS

For many years the standard preparation for bowel cleansing was a 4-liter or a 2-liter PEG electrolyte solution plus a laxative (eg, magnesium citrate, bisacodyl, or senna).1–3 The most frequent complaint heard from patients was that “the preparation is worse than the colonoscopy,” attributable to the taste and volume of the fluid they had to consume. Thus, compliance was often a significant issue with patients presenting for colonoscopy. In fact, inadequate bowel preparation is one of the most common reasons polyps are missed during colonoscopy.

Aqueous and tablet forms of NaP (sometimes with a laxative) have become a widely used alternative to PEG solutions because they require much less volume and as a result are more palatable, thereby improving compliance.4,5

NaP agents cleanse the colon by osmotically drawing plasma water into the bowel lumen. The patient must drink significant amounts of water or other oral solutions to prevent dehydration.

NaP-based bowel-cleansing agents are available in two forms: aqueous solution and tablet. Aqueous NaP (such as Fleet Phospho-soda) is a low-volume hyperosmotic solution containing 48 g of monobasic NaP and 18 g of dibasic NaP per 100 mL.6 An oral tablet form (such as Visicol and OsmoPrep) was developed to improve patient tolerance.7 Each 2-g tablet of Visicol contains 1,500 mg of active ingredients (monobasic and dibasic NaP) and 460 mg of microcrystalline cellulose, an inert polymer. Each OsmoPrep tablet contains 1,500 mg of the same active ingredients as Visicol, but the inert ingredients include PEG and magnesium stearate.

At first, the regimen was 40 tablets such as Visicol to be taken with water and bisacodyl. Subsequent regimens such as OsmoPrep with fewer tablets have been shown to be as effective and better tolerated.8 Microcrystalline cellulose in the tablet can produce a residue that may obscure the bowel mucosa. Newer preparations contain lower amounts of this inert ingredient, allowing for improved visualization of the colonic mucosa during colonoscopy.9

ADVANTAGES OF SODIUM PHOSPHATE BOWEL CLEANSERS

In a recent review article, Burke and Church10 noted that NaP cleansing regimens have been shown to be superior to PEG-electrolyte lavage solution with respect to tolerability and acceptance by patients, improved quality of bowel preparation, better mucosal visualization, and more efficient endoscopic examination. In addition, the volume of the preparation may also help decrease the risk of aspiration in some patients.2,3

DISADVANTAGES OF SODIUM PHOSPHATE AGENTS

Despite their comparable or better efficacy and their better tolerability, NaP agents have certain disadvantages.

Effects on the colonic mucosa

In rare cases NaP agents have been shown to alter the microscopic and macroscopic features of the colonic mucosa, and they can induce aphthoid erosions that may mimic those seen in inflammatory bowel disease and enteropathy or colopathy associated with nonsteroidal anti-inflammatory drugs (NSAIDs).11–13 Therefore, NaP agents should not be used prior to the initial endoscopic evaluation of patients with suspected inflammatory bowel disease, microscopic colitis, or NSAID-induced colonopathy.

Fluid and electrolyte shifts

Because NaP acts by drawing plasma water into the bowel lumen, significant volume and electrolyte shifts may occur.14,15 These can cause hypokalemia, hyperphosphatemia, hypocalcemia, hyponatremia or hypernatremia, hypomagnesemia, elevated blood urea nitrogen levels, decreased exercise capacity, increased plasma osmolarity,15–17 seizures,18 and acute renal failure with or without nephrocalcinosis.17,19–21

Thus, patients with significant comorbidities—such as a recent history of myocardial infarction, renal or hepatic insufficiency, or malnutrition—should not use NaP agents.22

Pivotal study of adverse events

In May 2006, the FDA issued an alert outlining the concerns of using oral NaP in specific patient populations. Of note were documented cases of acute phosphate nephropathy in 21 patients who used aqueous NaP (Fleet Phospho-Soda or Fleet Accu-Prep), and in 1 patient who used NaP tablets (Visicol).23 Acute renal injury was not limited to patients with preexisting renal insufficiency. It is uncertain whether this means that otherwise healthy people suffered renal injury or had risk factors besides renal insufficiency, since the data cited by the FDA report do not elucidate the possible risk factors for the development of nephropathy in patients with no preexisting renal insufficiency. So far, no cases of acute phosphate nephropathy or acute renal failure have been reported with OsmoPrep, a NaP tablet bowel preparation recently approved by the FDA.24 The long-term safety of OsmoPrep needs further evaluation.

 

 

PROCEED WITH CAUTION

Certain situations such as advanced age and cardiac, renal, and hepatic dysfunction call for extreme caution in the use of NaP bowel preparation agents. Therefore, it is recommended that patients with the following conditions should avoid using NaP agents for colon preparation:

  • Hepatic or renal insufficiency (there are no data as to the degree of hepatic or renal insufficiency)
  • Congestive heart failure
  • Over age 65
  • Dehydration or hypercalcemia
  • Chronic use of drugs that affect renal perfusion, such as NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or diuretics for hypertension.

Patients who take diuretics should not take them while they are using NaP for bowel preparation because of the risk of electrolyte abnormalities such as hypokalemia. In patients who have no alternative but to proceed with NaP preparation, our recommendation would be that the patient hold off taking diuretics, ACE inhibitors, and angiotensin receptor blockers while using the NaP prep. Given the importance of these medications in controlling diseases such as hypertension, the physician and the patient should jointly determine whether the benefits of using an NaP agent justify holding these drugs. We believe that patients taking these drugs should try using a PEG solution before considering NaP.

TASK FORCE GUIDELINES

Guidelines for using NaP bowel preparation agents, published by a task force of the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Society of American Gastrointestinal and Endoscopic Surgeons,25 include the following caveats:

  • Aqueous and tablet NaP colonic preparations are an alternative to PEG solutions, except in pediatric populations, patients over age 65, and those with bowel obstruction or other structural intestinal disorder, gut dysmotility, renal or hepatic insufficiency, congestive heart failure, or seizure disorder.
  • Dosing should be 45 mL in divided doses, 10 to 12 hours apart, with at least one dose taken on the morning of the procedure.25
  • The significant volume contraction and resulting dehydration seen in some patients using NaP preparations may be lessened by encouraging patients to drink fluids liberally during the days leading up to their procedure, and especially during NaP bowel preparation.26
  • NaP tablets should be dosed as 32 to 40 tablets. On the evening before the procedure the patient should take 20 tablets and then 12 to 20 tablets approximately 3 to 5 hours before undergoing endoscopy. The tablets should be taken four at a time every 15 minutes with approximately 8 oz of clear liquid.25

To maximize the efficacy and safety of colonoscopy, it is paramount that the colon be adequately prepared. Agents for bowel cleansing should be inexpensive, effective, safe, palatable, and easy to take. The most commonly used regimens are based on either PEG or NaP, and each has advantages and disadvantages (Table 1). The decision whether to use PEG or NaP for bowel cleansing should be individualized and should take into consideration the pros and cons of the agents and the patient’s general health.

Sodium phosphate (NaP) agents were introduced to provide a gentler alternative to polyethylene glycol (PEG) bowel preparations, which require patients to drink up to 4 liters of fluid over a few hours.

However, in May 2006 the US Food and Drug Administration (FDA) issued an alert that NaP products for bowel cleansing may, in some patients, pose a risk of acute phosphate nephropathy, a rare form of acute renal failure.

Although NaP preparations are generally safe and well tolerated, they can cause significant fluid shifts and electrolyte abnormalities. As such, they should not be used in patients with baseline electrolyte imbalances, renal or hepatic dysfunction, or a number of other comorbidities.

CURRENT BOWEL-CLEANSING OPTIONS

For many years the standard preparation for bowel cleansing was a 4-liter or a 2-liter PEG electrolyte solution plus a laxative (eg, magnesium citrate, bisacodyl, or senna).1–3 The most frequent complaint heard from patients was that “the preparation is worse than the colonoscopy,” attributable to the taste and volume of the fluid they had to consume. Thus, compliance was often a significant issue with patients presenting for colonoscopy. In fact, inadequate bowel preparation is one of the most common reasons polyps are missed during colonoscopy.

Aqueous and tablet forms of NaP (sometimes with a laxative) have become a widely used alternative to PEG solutions because they require much less volume and as a result are more palatable, thereby improving compliance.4,5

NaP agents cleanse the colon by osmotically drawing plasma water into the bowel lumen. The patient must drink significant amounts of water or other oral solutions to prevent dehydration.

NaP-based bowel-cleansing agents are available in two forms: aqueous solution and tablet. Aqueous NaP (such as Fleet Phospho-soda) is a low-volume hyperosmotic solution containing 48 g of monobasic NaP and 18 g of dibasic NaP per 100 mL.6 An oral tablet form (such as Visicol and OsmoPrep) was developed to improve patient tolerance.7 Each 2-g tablet of Visicol contains 1,500 mg of active ingredients (monobasic and dibasic NaP) and 460 mg of microcrystalline cellulose, an inert polymer. Each OsmoPrep tablet contains 1,500 mg of the same active ingredients as Visicol, but the inert ingredients include PEG and magnesium stearate.

At first, the regimen was 40 tablets such as Visicol to be taken with water and bisacodyl. Subsequent regimens such as OsmoPrep with fewer tablets have been shown to be as effective and better tolerated.8 Microcrystalline cellulose in the tablet can produce a residue that may obscure the bowel mucosa. Newer preparations contain lower amounts of this inert ingredient, allowing for improved visualization of the colonic mucosa during colonoscopy.9

ADVANTAGES OF SODIUM PHOSPHATE BOWEL CLEANSERS

In a recent review article, Burke and Church10 noted that NaP cleansing regimens have been shown to be superior to PEG-electrolyte lavage solution with respect to tolerability and acceptance by patients, improved quality of bowel preparation, better mucosal visualization, and more efficient endoscopic examination. In addition, the volume of the preparation may also help decrease the risk of aspiration in some patients.2,3

DISADVANTAGES OF SODIUM PHOSPHATE AGENTS

Despite their comparable or better efficacy and their better tolerability, NaP agents have certain disadvantages.

Effects on the colonic mucosa

In rare cases NaP agents have been shown to alter the microscopic and macroscopic features of the colonic mucosa, and they can induce aphthoid erosions that may mimic those seen in inflammatory bowel disease and enteropathy or colopathy associated with nonsteroidal anti-inflammatory drugs (NSAIDs).11–13 Therefore, NaP agents should not be used prior to the initial endoscopic evaluation of patients with suspected inflammatory bowel disease, microscopic colitis, or NSAID-induced colonopathy.

Fluid and electrolyte shifts

Because NaP acts by drawing plasma water into the bowel lumen, significant volume and electrolyte shifts may occur.14,15 These can cause hypokalemia, hyperphosphatemia, hypocalcemia, hyponatremia or hypernatremia, hypomagnesemia, elevated blood urea nitrogen levels, decreased exercise capacity, increased plasma osmolarity,15–17 seizures,18 and acute renal failure with or without nephrocalcinosis.17,19–21

Thus, patients with significant comorbidities—such as a recent history of myocardial infarction, renal or hepatic insufficiency, or malnutrition—should not use NaP agents.22

Pivotal study of adverse events

In May 2006, the FDA issued an alert outlining the concerns of using oral NaP in specific patient populations. Of note were documented cases of acute phosphate nephropathy in 21 patients who used aqueous NaP (Fleet Phospho-Soda or Fleet Accu-Prep), and in 1 patient who used NaP tablets (Visicol).23 Acute renal injury was not limited to patients with preexisting renal insufficiency. It is uncertain whether this means that otherwise healthy people suffered renal injury or had risk factors besides renal insufficiency, since the data cited by the FDA report do not elucidate the possible risk factors for the development of nephropathy in patients with no preexisting renal insufficiency. So far, no cases of acute phosphate nephropathy or acute renal failure have been reported with OsmoPrep, a NaP tablet bowel preparation recently approved by the FDA.24 The long-term safety of OsmoPrep needs further evaluation.

 

 

PROCEED WITH CAUTION

Certain situations such as advanced age and cardiac, renal, and hepatic dysfunction call for extreme caution in the use of NaP bowel preparation agents. Therefore, it is recommended that patients with the following conditions should avoid using NaP agents for colon preparation:

  • Hepatic or renal insufficiency (there are no data as to the degree of hepatic or renal insufficiency)
  • Congestive heart failure
  • Over age 65
  • Dehydration or hypercalcemia
  • Chronic use of drugs that affect renal perfusion, such as NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or diuretics for hypertension.

Patients who take diuretics should not take them while they are using NaP for bowel preparation because of the risk of electrolyte abnormalities such as hypokalemia. In patients who have no alternative but to proceed with NaP preparation, our recommendation would be that the patient hold off taking diuretics, ACE inhibitors, and angiotensin receptor blockers while using the NaP prep. Given the importance of these medications in controlling diseases such as hypertension, the physician and the patient should jointly determine whether the benefits of using an NaP agent justify holding these drugs. We believe that patients taking these drugs should try using a PEG solution before considering NaP.

TASK FORCE GUIDELINES

Guidelines for using NaP bowel preparation agents, published by a task force of the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Society of American Gastrointestinal and Endoscopic Surgeons,25 include the following caveats:

  • Aqueous and tablet NaP colonic preparations are an alternative to PEG solutions, except in pediatric populations, patients over age 65, and those with bowel obstruction or other structural intestinal disorder, gut dysmotility, renal or hepatic insufficiency, congestive heart failure, or seizure disorder.
  • Dosing should be 45 mL in divided doses, 10 to 12 hours apart, with at least one dose taken on the morning of the procedure.25
  • The significant volume contraction and resulting dehydration seen in some patients using NaP preparations may be lessened by encouraging patients to drink fluids liberally during the days leading up to their procedure, and especially during NaP bowel preparation.26
  • NaP tablets should be dosed as 32 to 40 tablets. On the evening before the procedure the patient should take 20 tablets and then 12 to 20 tablets approximately 3 to 5 hours before undergoing endoscopy. The tablets should be taken four at a time every 15 minutes with approximately 8 oz of clear liquid.25

To maximize the efficacy and safety of colonoscopy, it is paramount that the colon be adequately prepared. Agents for bowel cleansing should be inexpensive, effective, safe, palatable, and easy to take. The most commonly used regimens are based on either PEG or NaP, and each has advantages and disadvantages (Table 1). The decision whether to use PEG or NaP for bowel cleansing should be individualized and should take into consideration the pros and cons of the agents and the patient’s general health.

References
  1. Sharma VK, Chockalingham SK, Ugheoke EA, et al. Prospective, randomized, controlled comparison of the use of polyethylene glycol electrolyte lavage solution in four-liter versus two-liter volumes and pretreatment with either magnesium citrate or bisacodyl for colonoscopy preparation. Gastrointest Endosc 1998; 47:167171.
  2. Frommer D. Cleansing ability and tolerance of three bowel preparations for colonoscopy. Dis Colon Rectum 1997; 40:100104.
  3. Hsu CW, Imperiale TF. Meta-analysis and cost comparison of polyethylene glycol lavage versus sodium phosphate for colonoscopy preparation. Gastrointest Endosc 1998; 48:276282.
  4. Poon CM, Lee DWH, Mak SK, et al. Two liters of polyethylene glycol-electrolyte solution versus sodium phosphate as bowel cleansing regimen for colonoscopy: a prospective randomized controlled trial. Endoscopy 2002; 34:560563.
  5. Afridi SA, Barthel JS, King PD, et al. Prospective, randomized trial comparing a new sodium phosphate-bisacodyl regimen with conventional PEG-ES lavage for outpatient colonoscopy preparation. Gastrointest Endosc 1995; 41:485489.
  6. Schiller LR. Clinical pharmacology and use of laxatives and lavage solutions. J Clin Gastroenterol 1988; 28:1118.
  7. Kastenberg D, Chasen R, Choudhary C, et al. Efficacy and safety of sodium phosphate tablets compared with PEG solution in colon cleansing. Two identically designed, randomized, controlled, parallel group multicenter phase III trials. Gastrointest Endosc 2001; 54:705713.
  8. Rex DK, Chasen R, Pushpin MB. Safety and efficacy of two reduced dosing regimens of sodium phosphate tablets for preparation prior to colonoscopy. Aliment Pharmacol Ther 2002; 16:937944.
  9. Rex DK, Khashab M. Efficacy and tolerability of a new formulation of sodium phosphate tablets and a reduced sodium phosphate dose, in colon cleansing: a single-center open-label pilot trial. Aliment Pharmacol Ther 2005; 21:465468.
  10. Burke CA, Church JM. Enhancing the quality of colonoscopy: the importance of bowel purgatives. Gastrointest Endosc 2007; 66:565573.
  11. Rejchrt S, Bures J, Siroky M, et al. A prospective, observational study of colonic mucosal abnormalities associated with orally administered sodium phosphate for colon cleansing before colonoscopy. Gastrointest Endosc 2004; 59:651654.
  12. Hixson LJ. Colorectal ulcers associated with sodium phosphate catharsis. Gastrointest Endosc 1995; 42:101102.
  13. Zwas FR, Cirillo NW, El-Serag HB, Eisen RN. Colonic mucosal abnormalities associated with oral sodium phosphate solution. Gastrointest Endosc 1996; 43:463466.
  14. Clarkston WK, Tsen TN, Dies DF, Schratz CL, Vaswani SK, Bjerregaard P. Oral sodium phosphate versus sulfate-free polyethylene glycol electrolyte lavage solution in outpatient preparation for colonoscopy: a prospective comparison. Gastrointest Endosc 1996; 43:4248.
  15. Kolts BE, Lyles WE, Achem SR, et al. A comparison of the effectiveness and patient tolerance of oral sodium phosphate, castor oil, and standard electrolyte lavage for colonoscopy or sigmoidoscopy preparations. Am J Gastroenterol 1993; 88:12181223.
  16. Holte K, Neilsen KG, Madsen JL, Kehlet H. Physiologic effects of bowel preparation. Dis Colon Rectum 2004; 47:13971402.
  17. Clarkston WK, Tsen TN, Dies DF, et al. Oral sodium phosphate versus sulfate-free polyethylene glycol electrolyte lavage solution in outpatient preparation for colonoscopy: a prospective comparison. Gastrointest Endosc 1996; 43:4248.
  18. Frizelle FA, Colls BM. Hyponatremia and seizures after bowel preparation: report of three cases. Dis Colon Rectum 2005; 48:393396.
  19. Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004; 35:675684.
  20. Lieberman DA, Ghormley J, Flora K. Effect of oral sodium phosphate colon preparation on serum electrolytes in patients with normal serum creatinine. Gastrointest Endosc 1996; 43:467469.
  21. Gremse DA, Sacks AI, Raines S. Comparison of oral sodium phosphate to polyethylene-glycol-based solution for bowel preparation in children. J Pediatric Gastroenterol Nutr 1996; 23:586590.
  22. Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colonic cleanser. Drugs 2004; 64:16971714.
  23. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005; 16:33893396.
  24. FDA Alert. Patient information sheet. Oral sodium phosphate (OSP) products for bowel cleansing. 2006 May, Accessed January 8, 2008. www.fda.gov/CDER/drug/InfoSheets/patient/OSP_solutionPIS.htm.
  25. Wexner SD, Beck DE, Baron TH, et al. A consensus document on bowel preparation before colonoscopy prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Gastrointest Endosc 2006; 63:894909.
  26. Huynh T, Vanner S, Paterson W. Safety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia. Am J Gastroenterol 1995; 90:104107.
References
  1. Sharma VK, Chockalingham SK, Ugheoke EA, et al. Prospective, randomized, controlled comparison of the use of polyethylene glycol electrolyte lavage solution in four-liter versus two-liter volumes and pretreatment with either magnesium citrate or bisacodyl for colonoscopy preparation. Gastrointest Endosc 1998; 47:167171.
  2. Frommer D. Cleansing ability and tolerance of three bowel preparations for colonoscopy. Dis Colon Rectum 1997; 40:100104.
  3. Hsu CW, Imperiale TF. Meta-analysis and cost comparison of polyethylene glycol lavage versus sodium phosphate for colonoscopy preparation. Gastrointest Endosc 1998; 48:276282.
  4. Poon CM, Lee DWH, Mak SK, et al. Two liters of polyethylene glycol-electrolyte solution versus sodium phosphate as bowel cleansing regimen for colonoscopy: a prospective randomized controlled trial. Endoscopy 2002; 34:560563.
  5. Afridi SA, Barthel JS, King PD, et al. Prospective, randomized trial comparing a new sodium phosphate-bisacodyl regimen with conventional PEG-ES lavage for outpatient colonoscopy preparation. Gastrointest Endosc 1995; 41:485489.
  6. Schiller LR. Clinical pharmacology and use of laxatives and lavage solutions. J Clin Gastroenterol 1988; 28:1118.
  7. Kastenberg D, Chasen R, Choudhary C, et al. Efficacy and safety of sodium phosphate tablets compared with PEG solution in colon cleansing. Two identically designed, randomized, controlled, parallel group multicenter phase III trials. Gastrointest Endosc 2001; 54:705713.
  8. Rex DK, Chasen R, Pushpin MB. Safety and efficacy of two reduced dosing regimens of sodium phosphate tablets for preparation prior to colonoscopy. Aliment Pharmacol Ther 2002; 16:937944.
  9. Rex DK, Khashab M. Efficacy and tolerability of a new formulation of sodium phosphate tablets and a reduced sodium phosphate dose, in colon cleansing: a single-center open-label pilot trial. Aliment Pharmacol Ther 2005; 21:465468.
  10. Burke CA, Church JM. Enhancing the quality of colonoscopy: the importance of bowel purgatives. Gastrointest Endosc 2007; 66:565573.
  11. Rejchrt S, Bures J, Siroky M, et al. A prospective, observational study of colonic mucosal abnormalities associated with orally administered sodium phosphate for colon cleansing before colonoscopy. Gastrointest Endosc 2004; 59:651654.
  12. Hixson LJ. Colorectal ulcers associated with sodium phosphate catharsis. Gastrointest Endosc 1995; 42:101102.
  13. Zwas FR, Cirillo NW, El-Serag HB, Eisen RN. Colonic mucosal abnormalities associated with oral sodium phosphate solution. Gastrointest Endosc 1996; 43:463466.
  14. Clarkston WK, Tsen TN, Dies DF, Schratz CL, Vaswani SK, Bjerregaard P. Oral sodium phosphate versus sulfate-free polyethylene glycol electrolyte lavage solution in outpatient preparation for colonoscopy: a prospective comparison. Gastrointest Endosc 1996; 43:4248.
  15. Kolts BE, Lyles WE, Achem SR, et al. A comparison of the effectiveness and patient tolerance of oral sodium phosphate, castor oil, and standard electrolyte lavage for colonoscopy or sigmoidoscopy preparations. Am J Gastroenterol 1993; 88:12181223.
  16. Holte K, Neilsen KG, Madsen JL, Kehlet H. Physiologic effects of bowel preparation. Dis Colon Rectum 2004; 47:13971402.
  17. Clarkston WK, Tsen TN, Dies DF, et al. Oral sodium phosphate versus sulfate-free polyethylene glycol electrolyte lavage solution in outpatient preparation for colonoscopy: a prospective comparison. Gastrointest Endosc 1996; 43:4248.
  18. Frizelle FA, Colls BM. Hyponatremia and seizures after bowel preparation: report of three cases. Dis Colon Rectum 2005; 48:393396.
  19. Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004; 35:675684.
  20. Lieberman DA, Ghormley J, Flora K. Effect of oral sodium phosphate colon preparation on serum electrolytes in patients with normal serum creatinine. Gastrointest Endosc 1996; 43:467469.
  21. Gremse DA, Sacks AI, Raines S. Comparison of oral sodium phosphate to polyethylene-glycol-based solution for bowel preparation in children. J Pediatric Gastroenterol Nutr 1996; 23:586590.
  22. Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colonic cleanser. Drugs 2004; 64:16971714.
  23. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005; 16:33893396.
  24. FDA Alert. Patient information sheet. Oral sodium phosphate (OSP) products for bowel cleansing. 2006 May, Accessed January 8, 2008. www.fda.gov/CDER/drug/InfoSheets/patient/OSP_solutionPIS.htm.
  25. Wexner SD, Beck DE, Baron TH, et al. A consensus document on bowel preparation before colonoscopy prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Gastrointest Endosc 2006; 63:894909.
  26. Huynh T, Vanner S, Paterson W. Safety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia. Am J Gastroenterol 1995; 90:104107.
Issue
Cleveland Clinic Journal of Medicine - 75(3)
Issue
Cleveland Clinic Journal of Medicine - 75(3)
Page Number
173-176
Page Number
173-176
Publications
Publications
Topics
Article Type
Display Headline
What are the caveats to using sodium phosphate agents for bowel preparation?
Display Headline
What are the caveats to using sodium phosphate agents for bowel preparation?
Sections
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

A report from the department of staph affairs

Article Type
Changed
Tue, 04/17/2018 - 09:08
Display Headline
A report from the department of staph affairs

Evolution marches on, at least in the microbial world. In this issue of the Journal, Dr. Susan Rehm reviews some of the clinical manifestations and therapeutic dilemmas associated with methicillin-resistant Staphylococcus aureus (MRSA) infection.

Once, we worried about penicillin-resistant staph, but we had methicillin and several other effective antibiotics. Then, in the 1960s, MRSA started to appear. Intravenous drug abusers and then the chronically ill were favored hosts. Some hospitals became nests for MRSA. It began to acquire a reputation as a particularly nasty invader, associated with necrotizing pneumonia and resistant endocarditis. By 2004 more than 60% of staph isolates from critical care units were resistant to methicillin. But we had vancomycin.

Now, the hospital bugs are being reinforced by their community brethren—new strains from the suburbs that carry toxins that can damage tissue via stimulation of apoptosis of host cells. Most community-associated MRSA species are still sensitive to vancomycin (as well as to trimethoprim-sulfamethoxazole and clindamycin). But not all are. A growing community of bugs is relatively resistant to vancomycin and carries toxins—microbial suicide bombers with body armor.

The clinical presentation of necrotizing cellulitis, first appearing as a “spider bite,” is now seen in emergency wards around the country. In some cities, the overwhelming majority of deep skin infections evaluated in emergency rooms are due to MRSA. And patients with these infections, as well as asymptomatic nasal carriers of MRSA, are bringing these bugs into our hospitals.

The trends of emerging antibiotic resistance, discovery (and then perhaps overprescription) of new antibiotics, and changing patterns of staph infections are intimately intertwined. The evolutionary pressure that we humans are putting on S aureus with our antibiotics is taking this bug to a whole new place.

Article PDF
Author and Disclosure Information

Brian F. Mandell, MD, PhD
Editor in Chief

Issue
Cleveland Clinic Journal of Medicine - 75(3)
Publications
Topics
Page Number
166
Sections
Author and Disclosure Information

Brian F. Mandell, MD, PhD
Editor in Chief

Author and Disclosure Information

Brian F. Mandell, MD, PhD
Editor in Chief

Article PDF
Article PDF
Related Articles

Evolution marches on, at least in the microbial world. In this issue of the Journal, Dr. Susan Rehm reviews some of the clinical manifestations and therapeutic dilemmas associated with methicillin-resistant Staphylococcus aureus (MRSA) infection.

Once, we worried about penicillin-resistant staph, but we had methicillin and several other effective antibiotics. Then, in the 1960s, MRSA started to appear. Intravenous drug abusers and then the chronically ill were favored hosts. Some hospitals became nests for MRSA. It began to acquire a reputation as a particularly nasty invader, associated with necrotizing pneumonia and resistant endocarditis. By 2004 more than 60% of staph isolates from critical care units were resistant to methicillin. But we had vancomycin.

Now, the hospital bugs are being reinforced by their community brethren—new strains from the suburbs that carry toxins that can damage tissue via stimulation of apoptosis of host cells. Most community-associated MRSA species are still sensitive to vancomycin (as well as to trimethoprim-sulfamethoxazole and clindamycin). But not all are. A growing community of bugs is relatively resistant to vancomycin and carries toxins—microbial suicide bombers with body armor.

The clinical presentation of necrotizing cellulitis, first appearing as a “spider bite,” is now seen in emergency wards around the country. In some cities, the overwhelming majority of deep skin infections evaluated in emergency rooms are due to MRSA. And patients with these infections, as well as asymptomatic nasal carriers of MRSA, are bringing these bugs into our hospitals.

The trends of emerging antibiotic resistance, discovery (and then perhaps overprescription) of new antibiotics, and changing patterns of staph infections are intimately intertwined. The evolutionary pressure that we humans are putting on S aureus with our antibiotics is taking this bug to a whole new place.

Evolution marches on, at least in the microbial world. In this issue of the Journal, Dr. Susan Rehm reviews some of the clinical manifestations and therapeutic dilemmas associated with methicillin-resistant Staphylococcus aureus (MRSA) infection.

Once, we worried about penicillin-resistant staph, but we had methicillin and several other effective antibiotics. Then, in the 1960s, MRSA started to appear. Intravenous drug abusers and then the chronically ill were favored hosts. Some hospitals became nests for MRSA. It began to acquire a reputation as a particularly nasty invader, associated with necrotizing pneumonia and resistant endocarditis. By 2004 more than 60% of staph isolates from critical care units were resistant to methicillin. But we had vancomycin.

Now, the hospital bugs are being reinforced by their community brethren—new strains from the suburbs that carry toxins that can damage tissue via stimulation of apoptosis of host cells. Most community-associated MRSA species are still sensitive to vancomycin (as well as to trimethoprim-sulfamethoxazole and clindamycin). But not all are. A growing community of bugs is relatively resistant to vancomycin and carries toxins—microbial suicide bombers with body armor.

The clinical presentation of necrotizing cellulitis, first appearing as a “spider bite,” is now seen in emergency wards around the country. In some cities, the overwhelming majority of deep skin infections evaluated in emergency rooms are due to MRSA. And patients with these infections, as well as asymptomatic nasal carriers of MRSA, are bringing these bugs into our hospitals.

The trends of emerging antibiotic resistance, discovery (and then perhaps overprescription) of new antibiotics, and changing patterns of staph infections are intimately intertwined. The evolutionary pressure that we humans are putting on S aureus with our antibiotics is taking this bug to a whole new place.

Issue
Cleveland Clinic Journal of Medicine - 75(3)
Issue
Cleveland Clinic Journal of Medicine - 75(3)
Page Number
166
Page Number
166
Publications
Publications
Topics
Article Type
Display Headline
A report from the department of staph affairs
Display Headline
A report from the department of staph affairs
Sections
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

Staphylococcus aureus: The new adventures of a legendary pathogen

Article Type
Changed
Fri, 06/15/2018 - 06:44
Display Headline
Staphylococcus aureus: The new adventures of a legendary pathogen

Staphylococcus aureus is rearing its ugly head in new and interesting ways, both in the hospital and in the community.

Rates of invasive infections with methicillin-resistant S aureus (MRSA) have been increasing both in the hospital and in the community, a trend that has attracted considerable interest in the lay media. Curiously, the most common community-associated MRSA strain, which up to now has been distinct from hospital-associated MRSA strains, is invading our hospitals. Alarmingly, vancomycin (Vancocin), the drug of last resort for MRSA infections for the past 40 years, does not seem to be as effective as it used to be.

This paper summarizes the changing epidemiology of S aureus, particularly the emergence of MRSA outside of the hospital; reviews the difficulties associated with S aureus bacteremia and its treatment in view of; some changes in vancomycin susceptibility; and appraises the old and new treatment options.

MRSA IS ON THE RISE IN THE HOSPITAL

S aureus, a gram-positive, coagulase-positive bacterium, is one of the leading nosocomial bloodstream pathogens, second only to coagulase-negative staphylococci.1 And the incidence of S aureus infections is increasing. MRSA in particular is increasingly causing infections throughout hospitals, including intensive care units. As of 2004, nearly two-thirds of isolates of S aureus from intensive care units were MRSA.2

MRSA infections are worse than methicillin-susceptible S aureus (MSSA) infections in terms of the rates of death and other undesirable outcomes.3 Several factors may be responsible: MRSA infection may be a marker of severity of illness (sicker patients may be more likely to have MRSA), our treatment for MRSA may not be as effective as it is for MSSA, and the organism may be inherently more virulent.

METHICILLIN RESISTANCE IS ALSO ON THE RISE IN THE COMMUNITY

Community-associated MRSA began emerging clinically about 10 years ago. It was first described in a cohort of children with necrotizing pneumonia in Minnesota, but soon other populations at risk began to emerge, such as residents of correctional facilities, men who had sex with men, competitive athletes (eg, fencers, wrestlers, and football players), and Alaskan natives and other native populations. A common factor in all these groups was close proximity of the members to each other. Later, it began to spread beyond these traditional risk groups into the community at large.

Community-associated MRSA strains have a characteristic pattern of antimicrobial susceptibility (see below). In the laboratory, they grow somewhat faster than health-care-associated MRSA strains, but not as fast as MSSA. They have a strong association with skin and soft-tissue infections: when you see a skin or soft-tissue infection, be it in an outpatient or an inpatient, think about MRSA. Their virulence varies, but rapid onset and progression of illness are quite common. Their most common strain in the United States at present is USA 300.

Case 1: A young woman with necrotizing fasciitis

A 21-year-old college student presented to our service in May 2004 with high fever and severe arm pain, which had been worsening for several days. She had been previously healthy, had not had any contact with the health care system, and had not received any antibiotics.

Figure 1. Necrotizing fasciitis due to community-associated methicillin-resistant Staphylococcus aureus.
Her arm was red and extremely painful (Figure 1). Pain out of proportion to findings is a cardinal sign of necrotizing fasciitis, and this is indeed what she had.

Her blood cultures were positive for MRSA, as were cultures of the deep tissue of the deltoid muscle and fascia when she underwent emergency surgical debridement. The infection required several additional surgical debridements and removal of one head of her deltoid muscle, but she was fortunate: in the past, some patients with this problem might have undergone radical amputation of the arm or even more extensive surgery. This patient continued to have positive blood cultures 4 days postoperatively, but she ultimately recovered, completing 28 days of daptomycin (Cubicin) therapy at a dose of 6 mg/kg every 24 hours. The last 10 days of daptomycin therapy were given at home via a percutaneous intravenous central catheter.

Comment. The epidemiology of MRSA infections is changing. More patients who have no traditional risk factors, specifically health care contact, are getting MRSA infections. A recent report from the US Centers for Disease Control and Prevention (CDC) indicates that the proportion of patients with invasive disease due to MRSA has doubled since 2001–2002.4 Part of the reason undoubtedly is that MRSA, particularly community-associated MRSA, often carries specific virulence factors that make it more invasive. The CDC estimated that in 2005 there were nearly 100,000 cases of invasive MRSA infection in the United States, and nearly a fifth of these infections resulted in death.

 

 

Resistance and virulence factors in community-associated MRSA

Most community-associated MRSA strains carry a mobile genetic element called type IV SCCmec (staphylococcal chromosomal cassettemec) that enhances its antimicrobial resistance. This genetic component was probably borrowed from coagulase-negative staphylococci, in which it is quite common but does not cause as much of a problem. It is now present in a wide range of S aureus strains. Most of the S aureus strains that carry type IV SCCmec are MRSA, but a few MSSA strains do carry it as well.

The potent toxin Panton-Valentine leukocidin is an extracellular product that is detected in fewer than 5% of hospital strains but is more common in community-associated strains. It kills leukocytes by forming pores in the cell membrane and causing skin necrosis in cutaneous infections. It is associated with skin abscesses and rapidly progressive necrotizing pneumonia in MSSA or MRSA.

Epidemiologic differences between community- and health-care-associated MRSA

Patients with community-associated MRSA infections tend to be younger than those who traditionally get health-care-associated MRSA infections: in a study from Naimi et al in 2003, the mean ages were 23 vs 68 years.5 A greater proportion of patients with community-associated MRSA strains are nonwhite.4,5

Most community-associated MRSA infections are of the skin and soft tissue (75% in the series from Naimi et al5), but this pathogen causes other infections as well. Bacteremia of unknown origin has been seen, as has necrotizing pneumonia. Most of the skin and soft-tissue infections are relatively superficial, such as folliculitis or furunculosis, but deeper tissue infections such as necrotizing fasciitis and pyomyositis have also been seen.6

The incidence of community-associated MRSA infections varies greatly by geographic region.7 The northeastern United States has so far been relatively spared, but in Atlanta, Houston, and Los Angeles up to 80% of cases of characteristic skin or soft-tissue infections seen in emergency or outpatient departments are due to community-associated MRSA. Physicians at the Texas Children’s Hospital in Houston assume that all skin or soft-tissue infections are due to community-associated MRSA unless proven otherwise.8

Differences in antibiotic susceptibility

Community-associated MRSA is more susceptible to various antibiotics than health-care-associated MRSA,5 but not by much. Strains are usually susceptible to vancomycin, tetracyclines, trimethoprim-sulfamethoxazole (Bactrim, Septra), and rifampin (Rifadin). Unlike hospital strains, a fair number of community-acquired strains are susceptible to clindamycin (Cleocin) in the laboratory, but with a caveat: some of these clindamycin-susceptible strains actually may harbor the tools for inducible resistance. In fact, they can become resistant to clindamycin even without being exposed to it.

The laboratory test for inducible clindamycin resistance is called the D test. After coating an agar plate with S aureus, the technician places erythromycin and clindamycin disks. If the erythromycin induces clindamycin resistance, the plate is clear of growth around the clindamycin disk except for the portion nearest the erythromycin disk, leaving a characteristic D-shaped area of lucency.

Risk factors for MRSA

Moran et al7 analyzed the risk factors for community-associated MRSA in patients with skin or soft-tissue infections seen in the emergency department. The infection was more likely to be due to community-associated MRSA if the patient was black, had used any antibiotic in the past month, had a history of MRSA infection, or had close contact with a person with a similar infection. Many patients interpreted the infections as spider bites because the lesions tended to have a dark center surrounded by a tender area. These infections were not associated with underlying illness. In some cases, community-associated MRSA skin infections have been associated with tattooing and even manicuring.

However, it is very difficult to distinguish between community-associated MRSA and MSSA skin and soft-tissue infections on the basis of clinical and epidemiologic characteristics. Miller et al9 studied a large group of patients in Los Angeles who were hospitalized with community-associated skin and soft-tissue S aureus infections. All the patients were followed up for 30 days after hospital discharge. Regardless of whether they had MRSA or MSSA, they had similar outcomes. Close contacts of the patients also tended to develop infection.

A key point from this and many other studies: patients were more likely to remain infected if they did not undergo incision and drainage. This key intervention is indicated for any patient who has a skin and soft-tissue infection with an undrained focus of infection.

 

 

COMMUNITY-ASSOCIATED MRSA IS INVADING THE HOSPITAL

In a new development, community-associated MRSA strains are now appearing in the hospital. This is not only because patients are bacteremic when they come in: patients in the hospital are getting nosocomial infections due to community-associated MRSA strains.

Seybold et al10 analyzed 116 cases of MRSA bloodstream infections in Atlanta, GA. In 9 (8%) of the cases the patient had not had any contact with the health care system within the past year, and these cases were classified as truly community-associated. Of the remaining 107 cases, 49 (42%) were nosocomial, and the USA 300 strain—the predominant community-associated MRSA strain—accounted for 10 (20%) of the nosocomial cases.

In the recent CDC study of invasive MRSA infections, Klevens et al4 reported that nearly a third of cases of bacteremia were due to community-associated MRSA, and these strains accounted for a greater proportion of cases of cellulitis and endocarditis than did health-care-associated strains.

In a study of hospital-associated MRSA, Maree et al11 found that the percentage of cases in which the bacteria carried the SCCmec type IV marker had increased from less than 20% in 1999 to more than 50% in 2004.

Comment. Suffice it to say that we are surrounded by MRSA. Community-associated MRSA is here to stay. It is even invading our hospitals, and we need to consider this very carefully when choosing antimicrobial therapy.

NAGGING QUESTIONS ABOUT VANCOMYCIN

Case 2: Vancomycin-intermediate S aureus (VISA) bacteremia and endocarditis

In December 2006 we saw a very ill 60-year-old woman who was hospitalized with MRSA bacteremia, pacemaker endocarditis, and superior vena cava thrombosis. Although she was treated with vancomycin and rifampin, her condition worsened, she had a stroke, and she developed renal failure. In a difficult operation, the pacemaker was removed, but the bacteremia persisted. In early February 2007 she underwent another difficult operation in which the superior vena cava clot was debrided, a right atrial clot was removed, and her mitral valve was replaced. Less than 2 weeks later, and despite ongoing vancomycin and rifampin therapy, the MRSA bacteremia recurred.

During the approximately 6 weeks that the patient had been receiving these antibiotics, the minimal inhibitory concentration (MIC) of rifampin against the S aureus isolate increased from less than 1 μg/mL (susceptible) to 2 μg/mL (resistant). The MIC of vancomycin went from 2 μg/mL (susceptible) to 4 μg/mL (intermediately susceptible). Vancomycin and rifampin were discontinued, and daptomycin and gentamicin (Garamycin) therapy were started. (Her daptomycin MIC was 0.5 μg/mL). The patient’s condition stabilized, and she was discharged to a long-term nursing facility. She had no relapse of MRSA bacteremia, but she died in early April of that year.

Is vancomycin becoming less effective? Degrees of vancomycin resistance

Vancomycin has been our stalwart for treating MRSA infections for more than 40 years but it is not working as well as it used to, at least in certain situations.

Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:3040–3045
Figure 2. Population analysis of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate S aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-susceptible S aureus (VSSA). The population analysis shows how many cells in a fixed number of cells (usually about 107 colony-forming units [CFU]) of each strain are resistant to various concentrations of vancomycin. VRSA is a highly resistant and homogeneously resistant strain, with 100% of the population growing at each of the vancomycin concentrations tested. VISA is intermediately resistant, with 100% of the population growing at 4 μg of vancomycin per mL and also with significant subpopulations growing at 8 μg/mL. hVISA demonstrates heterogeneous resistance, having subpopulations of cells with various levels of resistance to vancomycin and including small populations of vancomycin-intermediate resistant cells with growth at 8 μg of vancomycin per mL.
Various terms describe the degrees of susceptibility or resistance to vancomycin (Figure 2).12

VRSA (vancomycin-resistant S aureus) is rare. These fully resistant strains probably acquired a resistance mechanism (the vanA operon) from vancomycin-resistant enterococci. Infections tend to occur in patients simultaneously infected with both S aureus and vancomycin-resistant enterococci, giving the bacteria an opportunity to exchange genetic material.

VISA (vancomycin-intermediate S aureus) infections tend to occur in patients like the one described above who have had long-term vancomycin therapy. VISA strains appear to overproduce a matrix that captures vancomycin and keeps it from entering the cell. On electron microscopy, these bacteria have a very thick cell wall.13

Vancomycin tolerance is a state in which the bacteria are “stunned” or kept in check but not killed by vancomycin. That is manifested in the laboratory by a ratio of minimum bactericidal concentration to MIC greater than 32.

hVISA (heteroresistant VISA) is new and worrisome. These organisms have an overall MIC in the susceptible range, but within that population are individual isolates with an MIC that is much higher—in the intermediate or perhaps even in the resistant range.14

Reported rates of hVISA vary from less than 2% to as high as 76%, because the methods for detecting it are still very poorly standardized. The usual automated laboratory tests do not detect hVISA.

hVISA is probably clinically relevant, as evidence is emerging both in vitro and in vivo that the higher the MIC for vancomycin, the worse the clinical outcome.15 hVISA has been associated with failures of therapy in several situations, usually in cases of severe invasive or deep infection, endocarditis, and bacteremia with vertebral osteomyelitis where vancomycin concentrations at the site of infection may be suboptimal.16–19 While most hVISA strains that have been described were resistant to methicillin, some were susceptible.

The E test is emerging as the standard test for hVISA. This test uses a plastic strip that contains gradually increasing concentrations of vancomycin along its length. Placed in the culture dish, the strip inhibits growth of the organism at its high-concentration end but not at its low-concentration end. If the sample contains hVISA, the cutoff is not well defined, with a few colonies growing at higher concentrations.

 

 

New definition of vancomycin susceptibility

Recognizing that the MICs for vancomycin have been rising in the last few years, the Clinical and Laboratory Standards Institute last year changed the break points between susceptibility and resistance. The new definitions are:

  • Susceptible—an MIC of 2.0 μg/mL or less (formerly 4.0 μg/mL or less)
  • Intermediate—4.0 to 8.0 μg/mL (formerly 8.0 to 16 μg/mL)
  • Resistant—16 μg/mL or greater (formerly 32 μg/mL or greater).

One should pay attention to the MIC numbers on the laboratory reports, not just to the words “susceptible” or “not susceptible.” If the number is, say, 0.5 μg/mL or less, the organism should really be susceptible. If the number is 1 or 2, it is still in the susceptible range, but those are the organisms that may cause problems later on.

Further, even if the vancomycin MIC is in the susceptible range, higher MICs may affect outcomes. The average duration of MRSA bacteremia on therapy is 8 to 9 days, vs 3 to 4 days with MSSA bacteremia.20,21 But Sakoulas et al15 found that, in MRSA bacteremia, the success rate with vancomycin therapy was 56% if the MIC was 0.5 or lower, compared with 10% if the MIC was 1.0 to 2.0 μg/mL. Examined in another way, the success rate was 50% if the logarithm of killing was 6.27 colony-forming units per mL or greater, 23% if 4.71 to 6.26, and zero if less than 4.71.

Case 3: Prolonged MRSA bacteremia

In the summer of 2006, a 66-year-old woman with a history of gastric bypass and cirrhosis underwent a long stay in the surgical intensive care unit because of a recurrent enterocutaneous fistula and chronic renal insufficiency. On November 5th, she had a positive blood culture for MRSA, which was treated appropriately with vancomycin for 4 weeks. She was discharged to subacute care but came back 2 days later, again with MRSA bacteremia. At that time her Hickman catheter, which had been inserted for total parenteral nutrition because of the enterocutaneous fistula, was removed.

Transthoracic echocardiography revealed no vegetations, but her bacteremia persisted. Her mental status was poor this entire time: she was mute and could barely be awakened. We looked for clots and infected clots; duplex ultrasonographic examinations of all four extremities were negative. Finally, magnetic resonance imaging of her back—performed empirically because of the persistent bacteremia—revealed vertebral osteomyelitis at level T12-L1. We also noticed on serial evaluations that the vancomycin MIC for her organism increased from 0.5 to 2.0 μg/mL, so therapy was changed from vancomycin to daptomycin.

Her bacteremia cleared. Follow-up echocardiography was negative, but she had two subsequent relapses of MRSA bacteremia, one in April 2007 and one before she died in the summer of 2007.

Prolonged bacteremia: Is it vancomycin resistance, or something else?

The MRSA isolates that cause prolonged bacteremia seem to have certain characteristics.22 Higher MICs are probably associated with longer periods of bacteremia. But some genetic components within some strains of S aureus give them a survival advantage. They have less susceptibility to the body’s thrombin-induced platelet microbicidal protein. These isolates are not only associated with prolonged bacteremia: they are also associated with osteomyelitis, deep abscesses, endocarditis, recurrent infection, and increased death rate.22 Clinical laboratories do not test for these genetic components. One wonders whether our patient may have had an isolate with these mutations that gave it a survival advantage.

Do not use vancomycin for MSSA

Avoid using vancomycin for MSSA infections. It has been shown time and time again that MSSA infections do not respond as well to vancomycin as they do to beta-lactam antibiotics, specifically to the semisynthetic penicillins such as oxacillin and nafcillin, and even some of the first-generation cephalosporins. Chang et al23 found that patients with MSSA bacteremia had higher rates of persistent infections, relapse, and bacteriologic failure if they received vancomycin than if they received nafcillin.

Do vancomycin trough levels affect toxicity?

The vancomycin trough levels that we aimed for in the past (5 to 10 μg/mL) were probably too low. Today, we aim for trough levels of 15 to 20 μg/mL, and many physicians are aiming for 20 to 25 μg/mL. Part of the reason is that vancomycin MICs are higher than they used to be: in order to keep the vancomycin level above the MIC for a longer period of time, the vancomycin trough level needs to be higher. In theory, keeping the vancomycin levels above the MIC for longer periods should improve outcomes. Yet Fowler et al22 found that vancomycin trough levels among patients who had persistent MRSA bacteremia were actually higher than trough levels among those in whom the bacteremia resolved, although the difference was not statistically significant.

We measure the vancomycin trough level to make sure it is high enough (and give larger doses if it is not); among adults, peak levels need not be monitored on a routine basis because of the predictable pharmacokinetics of vancomycin.

Vancomycin toxicity can be either idiosyncratic or synergistic. Idiosyncratic toxicity occurs when a patient who has been on vancomycin for a long time develops a fixed rash, not associated with infusion. This is an immunologic phenomenon. It is a rare and very serious situation and may require steroid therapy.

Synergistic toxicity occurs when vancomycin is given with other nephrotoxic agents, notably gentamicin. Vancomycin plus gentamicin equals nephrotoxicity. Vancomycin alone is usually not nephrotoxic, but close monitoring of renal function parameters is warranted with the use of higher doses.24

 

 

IN UNEXPLAINED BACTEREMIA, LOOK FOR ENDOCARDITIS

In blood cultures from patients with bacteremia, S aureus is never a contaminant. Even if just one blood culture is positive for S aureus, believe that S aureus is the culprit.

Reports in the 1950s suggested that at least half of patients who had S aureus bacteremia had endocarditis,25 leading to recommendations that all patients with S aureus bacteremia without an obvious primary source of infection should be evaluated for endocarditis. Subsequent estimates were lower, in the range of 15% to 25%.26,27 However, throughout the world S aureus endocarditis continues to have a very high mortality rate: at least a third of patients die.28

Clinical criteria (community acquisition, no primary focus, and metastatic sequelae) were developed to try to predict the risk of endocarditis in bacteremic patients.26 However, these criteria did not work very well. The clinical definition of endocarditis has evolved. The criteria of von Reyn et al29 from 1981 did not use echocardiography as part of the definition, but the 1994 Duke criteria,30 which were refined31 in 2000, use both clinical and echocardiographic parameters.

Stratton et al32 performed transthoracic echocardiography in 14 patients with bacteremia and found 1 patient with cryptic tricuspid infective endocarditis. Bayer et al33 subsequently reported that of 72 patients with bacteremia, 6 (18%) of those who had no clinical findings suggestive of infectious endocarditis had findings on echocardiography that led to changes in their regimen. Adding echocardiography to three clinical risk factors increased the sensitivity of diagnosing endocarditis from 70% to 85% with a specificity of 100% and predictive value of 96%.

The Duke criteria call for transesophageal echocardiography, which is not feasible in some patients, eg, those with cirrhosis and esophageal varices.

S aureus endocarditis has changed over the years as our patient population has changed, and MRSA endocarditis tends to hit some of our most vulnerable patients. In a study by Miro et al34 in 2005, MRSA was the leading pathogen in patients who were diagnosed with S aureus endocarditis in 1990 or later. We will only see these numbers go up. Patients with diabetes tend to have more MRSA, and of diabetic patients with MRSA endocarditis, 30% to 40% die in the hospital.

Indications for surgery

Certain conditions are indications for surgery among patients with endocarditis, and no antibiotic will cure the endocarditis if the patient has one of these conditions, eg:

  • Persistent bacteremia during antibiotic therapy
  • Recurrent emboli
  • Heart failure that cannot be controlled
  • Perivalvular or myocardial abscesses
  • Large vegetations
  • Early prosthetic valve infection
  • Certain arrhythmias.

How long should S aureus bacteremia be treated?

In cases of bacteremia in which endocarditis has been ruled out and removable foci of infection (eg, intravascular catheters) have been removed, some evidence indicates that treatment for 2 weeks would be as effective as the 4 to 6 weeks that we would use for endocarditis or other severe or invasive infections.35 The issue is controversial. If the patient has had frequent hospitalizations or a chronic medical condition I would hesitate to treat for less than 4 weeks, even if the infection appears to be associated with a removable focus.

Treatment of endocarditis

In the guidelines for treatment of endocarditis from the American Heart Association and Infectious Diseases Society of America,36 all the recommendations are relatively old and many of them are somewhat empiric—they are not based on evidence from randomized clinical trials. Rather, they are best opinions based on clinical experience and some observational studies over the years.

For MSSA. In cases of native-valve endocarditis, oxacillin (Bactocill), nafcillin (Unipen), or another semisynthetic beta-lactam antibiotic is recommended. For penicillin-allergic patients, we have other options, such as cefazolin (Ancef, Kefzol).

Combination therapy is frequently recommended for native valve endocarditis as well as for prosthetic valve endocarditis, with either rifampin or gentamicin along with a primary agent. There is some evidence that one can clear staphylococcal bacteremia a day or two more quickly by use of combination therapy with nafcillin plus an aminoglycoside than with nafcillin alone.37,38 For MSSA-associated endocarditis, vancomycin does not work as well as beta-lactam antibiotics.39,40

Korzeniowski and Sande37 and Chambers et al38 reported that the mean duration of bacteremia was 3.4 days for patients treated with nafcillin alone and 2.9 days for those treated with nafcillin plus an aminoglycoside. These studies led to consideration of a short course of gentamicin to clear the bacteremia quickly.

With MRSA, bacteremia often requires a week or more to clear. Levine et al21 reported a study in 42 patients, mostly injection-drug users, with right-sided native-valve endocarditis. The median duration of bacteremia was 7 days in patients who received vancomycin alone vs 9 days in those who received vancomycin plus rifampin; however, some patients were bacteremic for up to 27 days. Fever persisted for a median of 7 days, probably partly due to septic pulmonary emboli. Three patients died, and three required valve replacement.

 

 

NEW ANTIBIOTICS

Several new antibiotics are active against gram-positive cocci.41–44 However, the majority of them have not been prospectively studied for treating bacteremia or endocarditis.

Quinupristin/dalfopristin (Synercid) has not been formally studied for treatment of MRSA bacteremia or endocarditis. There are a few case reports of its use in these conditions.45 Quinupristin/dalfopristin is bacteriostatic, and its use may be associated with phlebitis, myalgias, and arthralgias.46

Linezolid (Zyvox) is approved for treatment of complicated skin and soft-tissue infections and for hospital-acquired pneumonia. There have been no specific studies of linezolid in the treatment of S aureus bacteremia or endocarditis. However, Shorr et al47 retrospectively looked at the bacteremic patients in five previous studies of linezolid vs vancomycin and found 144 cases of S aureus bacteremia, half of which were due to MRSA. Of 53 assessable patients with MRSA bacteremia, the primary infection was cured in 14 (56%) of the linezolid patients and 13 (46%) of the vancomycin patients.

The oral form is 100% bioavailable. One should avoid concomitant use of serotonin-reuptake inhibitors because of the risk of serotonin syndrome. Adverse effects include altered taste sensation and peripheral neuropathy. There are other potential toxicities, including hematologic changes (thrombocytopenia, leukopenia) and metabolic effects (lactic acidosis), so clinical and laboratory monitoring is important.48 The role of linezolid in the treatment of patients with S aureus bacteremia or endocarditis remains to be defined.

Daptomycin is indicated for complicated skin and soft-tissue infections, bacteremia, and right-sided endocarditis due to S aureus. Fowler et al20 found that daptomycin was not inferior to beta-lactam antibiotics for treatment of MSSA bacteremia and right-sided endocarditis, and for MRSA infections it outperformed vancomycin, but the difference was not statistically significant.

The dosing interval should be increased from once every 24 hours to every 48 hours if the creatinine clearance is 30 mL/minute or less. Adverse effects include myalgia, rhabdomyolysis (rare), and elevations in creatine phosphokinase. Reports of rising MICs during daptomycin therapy, in some cases associated with persistent infection,49 suggest that careful attention be paid to dosing and clinical monitoring.

Tigecycline (Tygacil) is indicated for complicated skin and soft-tissue infections and complicated intra-abdominal infections due to susceptible organisms. It is active against both MSSA and MRSA, but clinical experience with its use in invasive infections is somewhat limited.50 The dose of tigecycline should be reduced in advanced cirrhosis. Adverse effects include nausea and vomiting.

Telavancin, dalbavancin, and oritavancin, investigational parenteral antibiotics that are derivatives of vancomycin, are in clinical trials. The pharmacokinetic activity of these agents is of interest: telavancin is being studied with a once-daily dosing interval and dalbavancin’s half-life allows once-weekly dosing. In a limited trial, dalbavancin was found to be safe and effective in the treatment of catheter-related bloodstream infections.51 None of the antibiotics in this group has been studied for treatment of S aureus endocarditis. Telavancin therapy has been associated with rash, hypokalemia, QT prolongation, and creatinine elevations. Gastrointestinal symptoms have been reported with the use of dalbavancin.

Ceftobiprole, another investigational agent, is the only cephalosporin antibiotic that is active against MRSA. It is given every 12 hours. Adverse effects include nausea and taste disturbance.

Iclaprim is a novel diaminopyrimidine and a dihydrofolate reductase inhibitor. In vitro, it is active against gram-positive bacteria, including MRSA, VISA, and VRSA; clinical investigations at this point are limited to the treatment of skin and soft-tissue infections.

References
  1. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39:309371. Erratum in: Clin Infect Dis 2004; 39:1093.
  2. US Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance (NNIS) System. Campaign to prevent antimicrobial resistance. www.cdc.gov/drugresistance/healthcare/ha/HASlideSet.ppt.
  3. Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med 2002; 162:22292235.
  4. Klevens RM, Morrison MA, Nadle J, et al; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:17631771.
  5. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290:29762984.
  6. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352:14451453.
  7. Moran GJ, Krishnadasan A, Gorwitz RJ, et al EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666674.
  8. Mishaan AM, Mason EO, Martinez-Aquilar G, et al. Emergence of a predominant clone of community-acquired Staphylococcus aureus among children in Houston, Texas. Pediatr Infect Dis J 2005; 24:201206.
  9. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S. aureus infection: a prospective investigation. Clin Infect Dis 2007; 44:471482.
  10. Seybold U, Kourbatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis 2006; 42:647656.
  11. Maree CL, Daum RS, Boyle-Vavra S, Matayoshi K, Miller LG. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerg Infect Dis 2007; 13:236242.
  12. Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:30403045.
  13. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999; 340:517523.
  14. Schwaber MJ, Wright SB, Carmeli Y, et al. Clinical implications of varying degrees of vancomycin susceptibility in methicillin-resistant Staphylococcus aureus bacteremia. Emerg Infect Dis 2003; 9:657–664. Erratum in: Emerg Infect Dis 2004; 10:160.
  15. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004; 42:23982402.
  16. Naimi TS, Anderson D, O’Boyle C, et al. Vancomycin-intermediate Staphylococcus aureus with phenotypic susceptibility to methicillin in a patient with recurrent bacteremia. Clin Infect Dis 2003; 36:16091612.
  17. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother 2003; 47:12621266.
  18. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogenous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004; 38:448451.
  19. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521528.
  20. Fowler VG, Boucher HW, Corey GR, et al. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653665.
  21. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115:674680.
  22. Fowler VG, Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004; 190:11401149.
  23. Chang FY, Peacock JE, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore) 2003; 82:333339.
  24. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006; 166:21382144.
  25. Wilson R, Hamburger M. Fifteen years’ experience with staphylococcus septicemia in a large city hospital; analysis of fifty-five cases in the Cincinnati General Hospital 1940 to 1954. Am J Med 1957; 22:437457.
  26. Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med 1976; 60:495500.
  27. Shah M, Watanakunakorn C. Changing patterns of Staphylococcus aureus bacteremia. Am J Med Sci 1979; 278:115121.
  28. Fowler VG, Miro JM, Hoen B, et al ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293:30123021. Erratum in: JAMA 2005; 294:900.
  29. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: an analysis based on strict case definition. Ann Intern Med 1981; 94:505518.
  30. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200209.
  31. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633638.
  32. Stratton JR, Werner JA, Pearlman AS, Janko CL, Kliman S, Jackson MC. Bacteremia and the heart. Serial echocardiographic findings in 80 patients with documented or suspected bacteremia. Am J Med 1982; 73:851858.
  33. Bayer AS, Lam K, Ginzton L, Normal DC, Chiu CY, Ward JI. Staphylococcus aureus bacteremia. Clinical, serologic, and echocardiographic findings in patients with and without endocarditis. Arch Intern Med 1987; 147:457462.
  34. Miro JM, Anguera I, Cabell CH, et al International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database. Clin Infect Dis 2005; 41:507–514. Erratum in: Clin Infect Dis 2005; 41:10751077.
  35. Jernigan JA, Farr BM. Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis. Ann Intern Med 1993; 119:304311.
  36. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394e434. Erratum in: Circulation 2005; 112:2373. Circulation 2007; 115:e408.
  37. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982; 97:496503.
  38. Chambers HF, Korzeniowski OM, Sande MA. Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts. Medicine (Baltimore) 1983; 62:170177.
  39. Gentry CA, Rodvold KA, Novak RM, Hershow RC, Naderer OJ. Retrospective evaluation of therapies for Staphylococcus aureus endocarditis. Pharmacotherapy 1997; 17:990997.
  40. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34:12271231.
  41. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003; 36:473481.
  42. Rybak MJ. Therapeutic options for Gram-positive infections. J Hosp Infect 2001; 49 suppl A:S25S32.
  43. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2007; 45 suppl 3:S184S190.
  44. Appelbaum PC, Jacobs MR. Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria. Curr Opin Microbiol 2005; 8:510517.
  45. Drew RH, Perfect JR, Srinath L, Kirkimilis E, Dowzicky M, Talbot GH for the Synercid Emergency-Use Study Group. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. J Antimicrob Chemother 2000; 46:775784.
  46. Lamb HM, Figgitt DP, Faulds D. Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections. Drugs 1999; 58:10611097.
  47. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother 2005; 56:923929.
  48. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50:15991602.
  49. Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007; 45:601608.
  50. Munoz-Price LS, Lolans K, Quinn JP. Four cases of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections treated with tigecycline. Scand J Infect Dis 2006; 38:10811084.
  51. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis 2005; 40:37480.
Article PDF
Author and Disclosure Information

Susan J. Rehm, MD
Vice Chair Department of Infectious Disease; Executive Director, Physician Health, Cleveland Clinic

Address: Susan J. Rehm, MD, Department of Infectious Diseases, S32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. email [email protected]

Dr. Rehm has disclosed that she has served on the speaker’s bureaus of Cubist and Wyeth, has served on advisory boards for Cubist and Pfizer, and has received research support from Cubist.

Issue
Cleveland Clinic Journal of Medicine - 75(3)
Publications
Topics
Page Number
177-180, 183-186, 190-192
Sections
Author and Disclosure Information

Susan J. Rehm, MD
Vice Chair Department of Infectious Disease; Executive Director, Physician Health, Cleveland Clinic

Address: Susan J. Rehm, MD, Department of Infectious Diseases, S32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. email [email protected]

Dr. Rehm has disclosed that she has served on the speaker’s bureaus of Cubist and Wyeth, has served on advisory boards for Cubist and Pfizer, and has received research support from Cubist.

Author and Disclosure Information

Susan J. Rehm, MD
Vice Chair Department of Infectious Disease; Executive Director, Physician Health, Cleveland Clinic

Address: Susan J. Rehm, MD, Department of Infectious Diseases, S32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. email [email protected]

Dr. Rehm has disclosed that she has served on the speaker’s bureaus of Cubist and Wyeth, has served on advisory boards for Cubist and Pfizer, and has received research support from Cubist.

Article PDF
Article PDF

Staphylococcus aureus is rearing its ugly head in new and interesting ways, both in the hospital and in the community.

Rates of invasive infections with methicillin-resistant S aureus (MRSA) have been increasing both in the hospital and in the community, a trend that has attracted considerable interest in the lay media. Curiously, the most common community-associated MRSA strain, which up to now has been distinct from hospital-associated MRSA strains, is invading our hospitals. Alarmingly, vancomycin (Vancocin), the drug of last resort for MRSA infections for the past 40 years, does not seem to be as effective as it used to be.

This paper summarizes the changing epidemiology of S aureus, particularly the emergence of MRSA outside of the hospital; reviews the difficulties associated with S aureus bacteremia and its treatment in view of; some changes in vancomycin susceptibility; and appraises the old and new treatment options.

MRSA IS ON THE RISE IN THE HOSPITAL

S aureus, a gram-positive, coagulase-positive bacterium, is one of the leading nosocomial bloodstream pathogens, second only to coagulase-negative staphylococci.1 And the incidence of S aureus infections is increasing. MRSA in particular is increasingly causing infections throughout hospitals, including intensive care units. As of 2004, nearly two-thirds of isolates of S aureus from intensive care units were MRSA.2

MRSA infections are worse than methicillin-susceptible S aureus (MSSA) infections in terms of the rates of death and other undesirable outcomes.3 Several factors may be responsible: MRSA infection may be a marker of severity of illness (sicker patients may be more likely to have MRSA), our treatment for MRSA may not be as effective as it is for MSSA, and the organism may be inherently more virulent.

METHICILLIN RESISTANCE IS ALSO ON THE RISE IN THE COMMUNITY

Community-associated MRSA began emerging clinically about 10 years ago. It was first described in a cohort of children with necrotizing pneumonia in Minnesota, but soon other populations at risk began to emerge, such as residents of correctional facilities, men who had sex with men, competitive athletes (eg, fencers, wrestlers, and football players), and Alaskan natives and other native populations. A common factor in all these groups was close proximity of the members to each other. Later, it began to spread beyond these traditional risk groups into the community at large.

Community-associated MRSA strains have a characteristic pattern of antimicrobial susceptibility (see below). In the laboratory, they grow somewhat faster than health-care-associated MRSA strains, but not as fast as MSSA. They have a strong association with skin and soft-tissue infections: when you see a skin or soft-tissue infection, be it in an outpatient or an inpatient, think about MRSA. Their virulence varies, but rapid onset and progression of illness are quite common. Their most common strain in the United States at present is USA 300.

Case 1: A young woman with necrotizing fasciitis

A 21-year-old college student presented to our service in May 2004 with high fever and severe arm pain, which had been worsening for several days. She had been previously healthy, had not had any contact with the health care system, and had not received any antibiotics.

Figure 1. Necrotizing fasciitis due to community-associated methicillin-resistant Staphylococcus aureus.
Her arm was red and extremely painful (Figure 1). Pain out of proportion to findings is a cardinal sign of necrotizing fasciitis, and this is indeed what she had.

Her blood cultures were positive for MRSA, as were cultures of the deep tissue of the deltoid muscle and fascia when she underwent emergency surgical debridement. The infection required several additional surgical debridements and removal of one head of her deltoid muscle, but she was fortunate: in the past, some patients with this problem might have undergone radical amputation of the arm or even more extensive surgery. This patient continued to have positive blood cultures 4 days postoperatively, but she ultimately recovered, completing 28 days of daptomycin (Cubicin) therapy at a dose of 6 mg/kg every 24 hours. The last 10 days of daptomycin therapy were given at home via a percutaneous intravenous central catheter.

Comment. The epidemiology of MRSA infections is changing. More patients who have no traditional risk factors, specifically health care contact, are getting MRSA infections. A recent report from the US Centers for Disease Control and Prevention (CDC) indicates that the proportion of patients with invasive disease due to MRSA has doubled since 2001–2002.4 Part of the reason undoubtedly is that MRSA, particularly community-associated MRSA, often carries specific virulence factors that make it more invasive. The CDC estimated that in 2005 there were nearly 100,000 cases of invasive MRSA infection in the United States, and nearly a fifth of these infections resulted in death.

 

 

Resistance and virulence factors in community-associated MRSA

Most community-associated MRSA strains carry a mobile genetic element called type IV SCCmec (staphylococcal chromosomal cassettemec) that enhances its antimicrobial resistance. This genetic component was probably borrowed from coagulase-negative staphylococci, in which it is quite common but does not cause as much of a problem. It is now present in a wide range of S aureus strains. Most of the S aureus strains that carry type IV SCCmec are MRSA, but a few MSSA strains do carry it as well.

The potent toxin Panton-Valentine leukocidin is an extracellular product that is detected in fewer than 5% of hospital strains but is more common in community-associated strains. It kills leukocytes by forming pores in the cell membrane and causing skin necrosis in cutaneous infections. It is associated with skin abscesses and rapidly progressive necrotizing pneumonia in MSSA or MRSA.

Epidemiologic differences between community- and health-care-associated MRSA

Patients with community-associated MRSA infections tend to be younger than those who traditionally get health-care-associated MRSA infections: in a study from Naimi et al in 2003, the mean ages were 23 vs 68 years.5 A greater proportion of patients with community-associated MRSA strains are nonwhite.4,5

Most community-associated MRSA infections are of the skin and soft tissue (75% in the series from Naimi et al5), but this pathogen causes other infections as well. Bacteremia of unknown origin has been seen, as has necrotizing pneumonia. Most of the skin and soft-tissue infections are relatively superficial, such as folliculitis or furunculosis, but deeper tissue infections such as necrotizing fasciitis and pyomyositis have also been seen.6

The incidence of community-associated MRSA infections varies greatly by geographic region.7 The northeastern United States has so far been relatively spared, but in Atlanta, Houston, and Los Angeles up to 80% of cases of characteristic skin or soft-tissue infections seen in emergency or outpatient departments are due to community-associated MRSA. Physicians at the Texas Children’s Hospital in Houston assume that all skin or soft-tissue infections are due to community-associated MRSA unless proven otherwise.8

Differences in antibiotic susceptibility

Community-associated MRSA is more susceptible to various antibiotics than health-care-associated MRSA,5 but not by much. Strains are usually susceptible to vancomycin, tetracyclines, trimethoprim-sulfamethoxazole (Bactrim, Septra), and rifampin (Rifadin). Unlike hospital strains, a fair number of community-acquired strains are susceptible to clindamycin (Cleocin) in the laboratory, but with a caveat: some of these clindamycin-susceptible strains actually may harbor the tools for inducible resistance. In fact, they can become resistant to clindamycin even without being exposed to it.

The laboratory test for inducible clindamycin resistance is called the D test. After coating an agar plate with S aureus, the technician places erythromycin and clindamycin disks. If the erythromycin induces clindamycin resistance, the plate is clear of growth around the clindamycin disk except for the portion nearest the erythromycin disk, leaving a characteristic D-shaped area of lucency.

Risk factors for MRSA

Moran et al7 analyzed the risk factors for community-associated MRSA in patients with skin or soft-tissue infections seen in the emergency department. The infection was more likely to be due to community-associated MRSA if the patient was black, had used any antibiotic in the past month, had a history of MRSA infection, or had close contact with a person with a similar infection. Many patients interpreted the infections as spider bites because the lesions tended to have a dark center surrounded by a tender area. These infections were not associated with underlying illness. In some cases, community-associated MRSA skin infections have been associated with tattooing and even manicuring.

However, it is very difficult to distinguish between community-associated MRSA and MSSA skin and soft-tissue infections on the basis of clinical and epidemiologic characteristics. Miller et al9 studied a large group of patients in Los Angeles who were hospitalized with community-associated skin and soft-tissue S aureus infections. All the patients were followed up for 30 days after hospital discharge. Regardless of whether they had MRSA or MSSA, they had similar outcomes. Close contacts of the patients also tended to develop infection.

A key point from this and many other studies: patients were more likely to remain infected if they did not undergo incision and drainage. This key intervention is indicated for any patient who has a skin and soft-tissue infection with an undrained focus of infection.

 

 

COMMUNITY-ASSOCIATED MRSA IS INVADING THE HOSPITAL

In a new development, community-associated MRSA strains are now appearing in the hospital. This is not only because patients are bacteremic when they come in: patients in the hospital are getting nosocomial infections due to community-associated MRSA strains.

Seybold et al10 analyzed 116 cases of MRSA bloodstream infections in Atlanta, GA. In 9 (8%) of the cases the patient had not had any contact with the health care system within the past year, and these cases were classified as truly community-associated. Of the remaining 107 cases, 49 (42%) were nosocomial, and the USA 300 strain—the predominant community-associated MRSA strain—accounted for 10 (20%) of the nosocomial cases.

In the recent CDC study of invasive MRSA infections, Klevens et al4 reported that nearly a third of cases of bacteremia were due to community-associated MRSA, and these strains accounted for a greater proportion of cases of cellulitis and endocarditis than did health-care-associated strains.

In a study of hospital-associated MRSA, Maree et al11 found that the percentage of cases in which the bacteria carried the SCCmec type IV marker had increased from less than 20% in 1999 to more than 50% in 2004.

Comment. Suffice it to say that we are surrounded by MRSA. Community-associated MRSA is here to stay. It is even invading our hospitals, and we need to consider this very carefully when choosing antimicrobial therapy.

NAGGING QUESTIONS ABOUT VANCOMYCIN

Case 2: Vancomycin-intermediate S aureus (VISA) bacteremia and endocarditis

In December 2006 we saw a very ill 60-year-old woman who was hospitalized with MRSA bacteremia, pacemaker endocarditis, and superior vena cava thrombosis. Although she was treated with vancomycin and rifampin, her condition worsened, she had a stroke, and she developed renal failure. In a difficult operation, the pacemaker was removed, but the bacteremia persisted. In early February 2007 she underwent another difficult operation in which the superior vena cava clot was debrided, a right atrial clot was removed, and her mitral valve was replaced. Less than 2 weeks later, and despite ongoing vancomycin and rifampin therapy, the MRSA bacteremia recurred.

During the approximately 6 weeks that the patient had been receiving these antibiotics, the minimal inhibitory concentration (MIC) of rifampin against the S aureus isolate increased from less than 1 μg/mL (susceptible) to 2 μg/mL (resistant). The MIC of vancomycin went from 2 μg/mL (susceptible) to 4 μg/mL (intermediately susceptible). Vancomycin and rifampin were discontinued, and daptomycin and gentamicin (Garamycin) therapy were started. (Her daptomycin MIC was 0.5 μg/mL). The patient’s condition stabilized, and she was discharged to a long-term nursing facility. She had no relapse of MRSA bacteremia, but she died in early April of that year.

Is vancomycin becoming less effective? Degrees of vancomycin resistance

Vancomycin has been our stalwart for treating MRSA infections for more than 40 years but it is not working as well as it used to, at least in certain situations.

Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:3040–3045
Figure 2. Population analysis of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate S aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-susceptible S aureus (VSSA). The population analysis shows how many cells in a fixed number of cells (usually about 107 colony-forming units [CFU]) of each strain are resistant to various concentrations of vancomycin. VRSA is a highly resistant and homogeneously resistant strain, with 100% of the population growing at each of the vancomycin concentrations tested. VISA is intermediately resistant, with 100% of the population growing at 4 μg of vancomycin per mL and also with significant subpopulations growing at 8 μg/mL. hVISA demonstrates heterogeneous resistance, having subpopulations of cells with various levels of resistance to vancomycin and including small populations of vancomycin-intermediate resistant cells with growth at 8 μg of vancomycin per mL.
Various terms describe the degrees of susceptibility or resistance to vancomycin (Figure 2).12

VRSA (vancomycin-resistant S aureus) is rare. These fully resistant strains probably acquired a resistance mechanism (the vanA operon) from vancomycin-resistant enterococci. Infections tend to occur in patients simultaneously infected with both S aureus and vancomycin-resistant enterococci, giving the bacteria an opportunity to exchange genetic material.

VISA (vancomycin-intermediate S aureus) infections tend to occur in patients like the one described above who have had long-term vancomycin therapy. VISA strains appear to overproduce a matrix that captures vancomycin and keeps it from entering the cell. On electron microscopy, these bacteria have a very thick cell wall.13

Vancomycin tolerance is a state in which the bacteria are “stunned” or kept in check but not killed by vancomycin. That is manifested in the laboratory by a ratio of minimum bactericidal concentration to MIC greater than 32.

hVISA (heteroresistant VISA) is new and worrisome. These organisms have an overall MIC in the susceptible range, but within that population are individual isolates with an MIC that is much higher—in the intermediate or perhaps even in the resistant range.14

Reported rates of hVISA vary from less than 2% to as high as 76%, because the methods for detecting it are still very poorly standardized. The usual automated laboratory tests do not detect hVISA.

hVISA is probably clinically relevant, as evidence is emerging both in vitro and in vivo that the higher the MIC for vancomycin, the worse the clinical outcome.15 hVISA has been associated with failures of therapy in several situations, usually in cases of severe invasive or deep infection, endocarditis, and bacteremia with vertebral osteomyelitis where vancomycin concentrations at the site of infection may be suboptimal.16–19 While most hVISA strains that have been described were resistant to methicillin, some were susceptible.

The E test is emerging as the standard test for hVISA. This test uses a plastic strip that contains gradually increasing concentrations of vancomycin along its length. Placed in the culture dish, the strip inhibits growth of the organism at its high-concentration end but not at its low-concentration end. If the sample contains hVISA, the cutoff is not well defined, with a few colonies growing at higher concentrations.

 

 

New definition of vancomycin susceptibility

Recognizing that the MICs for vancomycin have been rising in the last few years, the Clinical and Laboratory Standards Institute last year changed the break points between susceptibility and resistance. The new definitions are:

  • Susceptible—an MIC of 2.0 μg/mL or less (formerly 4.0 μg/mL or less)
  • Intermediate—4.0 to 8.0 μg/mL (formerly 8.0 to 16 μg/mL)
  • Resistant—16 μg/mL or greater (formerly 32 μg/mL or greater).

One should pay attention to the MIC numbers on the laboratory reports, not just to the words “susceptible” or “not susceptible.” If the number is, say, 0.5 μg/mL or less, the organism should really be susceptible. If the number is 1 or 2, it is still in the susceptible range, but those are the organisms that may cause problems later on.

Further, even if the vancomycin MIC is in the susceptible range, higher MICs may affect outcomes. The average duration of MRSA bacteremia on therapy is 8 to 9 days, vs 3 to 4 days with MSSA bacteremia.20,21 But Sakoulas et al15 found that, in MRSA bacteremia, the success rate with vancomycin therapy was 56% if the MIC was 0.5 or lower, compared with 10% if the MIC was 1.0 to 2.0 μg/mL. Examined in another way, the success rate was 50% if the logarithm of killing was 6.27 colony-forming units per mL or greater, 23% if 4.71 to 6.26, and zero if less than 4.71.

Case 3: Prolonged MRSA bacteremia

In the summer of 2006, a 66-year-old woman with a history of gastric bypass and cirrhosis underwent a long stay in the surgical intensive care unit because of a recurrent enterocutaneous fistula and chronic renal insufficiency. On November 5th, she had a positive blood culture for MRSA, which was treated appropriately with vancomycin for 4 weeks. She was discharged to subacute care but came back 2 days later, again with MRSA bacteremia. At that time her Hickman catheter, which had been inserted for total parenteral nutrition because of the enterocutaneous fistula, was removed.

Transthoracic echocardiography revealed no vegetations, but her bacteremia persisted. Her mental status was poor this entire time: she was mute and could barely be awakened. We looked for clots and infected clots; duplex ultrasonographic examinations of all four extremities were negative. Finally, magnetic resonance imaging of her back—performed empirically because of the persistent bacteremia—revealed vertebral osteomyelitis at level T12-L1. We also noticed on serial evaluations that the vancomycin MIC for her organism increased from 0.5 to 2.0 μg/mL, so therapy was changed from vancomycin to daptomycin.

Her bacteremia cleared. Follow-up echocardiography was negative, but she had two subsequent relapses of MRSA bacteremia, one in April 2007 and one before she died in the summer of 2007.

Prolonged bacteremia: Is it vancomycin resistance, or something else?

The MRSA isolates that cause prolonged bacteremia seem to have certain characteristics.22 Higher MICs are probably associated with longer periods of bacteremia. But some genetic components within some strains of S aureus give them a survival advantage. They have less susceptibility to the body’s thrombin-induced platelet microbicidal protein. These isolates are not only associated with prolonged bacteremia: they are also associated with osteomyelitis, deep abscesses, endocarditis, recurrent infection, and increased death rate.22 Clinical laboratories do not test for these genetic components. One wonders whether our patient may have had an isolate with these mutations that gave it a survival advantage.

Do not use vancomycin for MSSA

Avoid using vancomycin for MSSA infections. It has been shown time and time again that MSSA infections do not respond as well to vancomycin as they do to beta-lactam antibiotics, specifically to the semisynthetic penicillins such as oxacillin and nafcillin, and even some of the first-generation cephalosporins. Chang et al23 found that patients with MSSA bacteremia had higher rates of persistent infections, relapse, and bacteriologic failure if they received vancomycin than if they received nafcillin.

Do vancomycin trough levels affect toxicity?

The vancomycin trough levels that we aimed for in the past (5 to 10 μg/mL) were probably too low. Today, we aim for trough levels of 15 to 20 μg/mL, and many physicians are aiming for 20 to 25 μg/mL. Part of the reason is that vancomycin MICs are higher than they used to be: in order to keep the vancomycin level above the MIC for a longer period of time, the vancomycin trough level needs to be higher. In theory, keeping the vancomycin levels above the MIC for longer periods should improve outcomes. Yet Fowler et al22 found that vancomycin trough levels among patients who had persistent MRSA bacteremia were actually higher than trough levels among those in whom the bacteremia resolved, although the difference was not statistically significant.

We measure the vancomycin trough level to make sure it is high enough (and give larger doses if it is not); among adults, peak levels need not be monitored on a routine basis because of the predictable pharmacokinetics of vancomycin.

Vancomycin toxicity can be either idiosyncratic or synergistic. Idiosyncratic toxicity occurs when a patient who has been on vancomycin for a long time develops a fixed rash, not associated with infusion. This is an immunologic phenomenon. It is a rare and very serious situation and may require steroid therapy.

Synergistic toxicity occurs when vancomycin is given with other nephrotoxic agents, notably gentamicin. Vancomycin plus gentamicin equals nephrotoxicity. Vancomycin alone is usually not nephrotoxic, but close monitoring of renal function parameters is warranted with the use of higher doses.24

 

 

IN UNEXPLAINED BACTEREMIA, LOOK FOR ENDOCARDITIS

In blood cultures from patients with bacteremia, S aureus is never a contaminant. Even if just one blood culture is positive for S aureus, believe that S aureus is the culprit.

Reports in the 1950s suggested that at least half of patients who had S aureus bacteremia had endocarditis,25 leading to recommendations that all patients with S aureus bacteremia without an obvious primary source of infection should be evaluated for endocarditis. Subsequent estimates were lower, in the range of 15% to 25%.26,27 However, throughout the world S aureus endocarditis continues to have a very high mortality rate: at least a third of patients die.28

Clinical criteria (community acquisition, no primary focus, and metastatic sequelae) were developed to try to predict the risk of endocarditis in bacteremic patients.26 However, these criteria did not work very well. The clinical definition of endocarditis has evolved. The criteria of von Reyn et al29 from 1981 did not use echocardiography as part of the definition, but the 1994 Duke criteria,30 which were refined31 in 2000, use both clinical and echocardiographic parameters.

Stratton et al32 performed transthoracic echocardiography in 14 patients with bacteremia and found 1 patient with cryptic tricuspid infective endocarditis. Bayer et al33 subsequently reported that of 72 patients with bacteremia, 6 (18%) of those who had no clinical findings suggestive of infectious endocarditis had findings on echocardiography that led to changes in their regimen. Adding echocardiography to three clinical risk factors increased the sensitivity of diagnosing endocarditis from 70% to 85% with a specificity of 100% and predictive value of 96%.

The Duke criteria call for transesophageal echocardiography, which is not feasible in some patients, eg, those with cirrhosis and esophageal varices.

S aureus endocarditis has changed over the years as our patient population has changed, and MRSA endocarditis tends to hit some of our most vulnerable patients. In a study by Miro et al34 in 2005, MRSA was the leading pathogen in patients who were diagnosed with S aureus endocarditis in 1990 or later. We will only see these numbers go up. Patients with diabetes tend to have more MRSA, and of diabetic patients with MRSA endocarditis, 30% to 40% die in the hospital.

Indications for surgery

Certain conditions are indications for surgery among patients with endocarditis, and no antibiotic will cure the endocarditis if the patient has one of these conditions, eg:

  • Persistent bacteremia during antibiotic therapy
  • Recurrent emboli
  • Heart failure that cannot be controlled
  • Perivalvular or myocardial abscesses
  • Large vegetations
  • Early prosthetic valve infection
  • Certain arrhythmias.

How long should S aureus bacteremia be treated?

In cases of bacteremia in which endocarditis has been ruled out and removable foci of infection (eg, intravascular catheters) have been removed, some evidence indicates that treatment for 2 weeks would be as effective as the 4 to 6 weeks that we would use for endocarditis or other severe or invasive infections.35 The issue is controversial. If the patient has had frequent hospitalizations or a chronic medical condition I would hesitate to treat for less than 4 weeks, even if the infection appears to be associated with a removable focus.

Treatment of endocarditis

In the guidelines for treatment of endocarditis from the American Heart Association and Infectious Diseases Society of America,36 all the recommendations are relatively old and many of them are somewhat empiric—they are not based on evidence from randomized clinical trials. Rather, they are best opinions based on clinical experience and some observational studies over the years.

For MSSA. In cases of native-valve endocarditis, oxacillin (Bactocill), nafcillin (Unipen), or another semisynthetic beta-lactam antibiotic is recommended. For penicillin-allergic patients, we have other options, such as cefazolin (Ancef, Kefzol).

Combination therapy is frequently recommended for native valve endocarditis as well as for prosthetic valve endocarditis, with either rifampin or gentamicin along with a primary agent. There is some evidence that one can clear staphylococcal bacteremia a day or two more quickly by use of combination therapy with nafcillin plus an aminoglycoside than with nafcillin alone.37,38 For MSSA-associated endocarditis, vancomycin does not work as well as beta-lactam antibiotics.39,40

Korzeniowski and Sande37 and Chambers et al38 reported that the mean duration of bacteremia was 3.4 days for patients treated with nafcillin alone and 2.9 days for those treated with nafcillin plus an aminoglycoside. These studies led to consideration of a short course of gentamicin to clear the bacteremia quickly.

With MRSA, bacteremia often requires a week or more to clear. Levine et al21 reported a study in 42 patients, mostly injection-drug users, with right-sided native-valve endocarditis. The median duration of bacteremia was 7 days in patients who received vancomycin alone vs 9 days in those who received vancomycin plus rifampin; however, some patients were bacteremic for up to 27 days. Fever persisted for a median of 7 days, probably partly due to septic pulmonary emboli. Three patients died, and three required valve replacement.

 

 

NEW ANTIBIOTICS

Several new antibiotics are active against gram-positive cocci.41–44 However, the majority of them have not been prospectively studied for treating bacteremia or endocarditis.

Quinupristin/dalfopristin (Synercid) has not been formally studied for treatment of MRSA bacteremia or endocarditis. There are a few case reports of its use in these conditions.45 Quinupristin/dalfopristin is bacteriostatic, and its use may be associated with phlebitis, myalgias, and arthralgias.46

Linezolid (Zyvox) is approved for treatment of complicated skin and soft-tissue infections and for hospital-acquired pneumonia. There have been no specific studies of linezolid in the treatment of S aureus bacteremia or endocarditis. However, Shorr et al47 retrospectively looked at the bacteremic patients in five previous studies of linezolid vs vancomycin and found 144 cases of S aureus bacteremia, half of which were due to MRSA. Of 53 assessable patients with MRSA bacteremia, the primary infection was cured in 14 (56%) of the linezolid patients and 13 (46%) of the vancomycin patients.

The oral form is 100% bioavailable. One should avoid concomitant use of serotonin-reuptake inhibitors because of the risk of serotonin syndrome. Adverse effects include altered taste sensation and peripheral neuropathy. There are other potential toxicities, including hematologic changes (thrombocytopenia, leukopenia) and metabolic effects (lactic acidosis), so clinical and laboratory monitoring is important.48 The role of linezolid in the treatment of patients with S aureus bacteremia or endocarditis remains to be defined.

Daptomycin is indicated for complicated skin and soft-tissue infections, bacteremia, and right-sided endocarditis due to S aureus. Fowler et al20 found that daptomycin was not inferior to beta-lactam antibiotics for treatment of MSSA bacteremia and right-sided endocarditis, and for MRSA infections it outperformed vancomycin, but the difference was not statistically significant.

The dosing interval should be increased from once every 24 hours to every 48 hours if the creatinine clearance is 30 mL/minute or less. Adverse effects include myalgia, rhabdomyolysis (rare), and elevations in creatine phosphokinase. Reports of rising MICs during daptomycin therapy, in some cases associated with persistent infection,49 suggest that careful attention be paid to dosing and clinical monitoring.

Tigecycline (Tygacil) is indicated for complicated skin and soft-tissue infections and complicated intra-abdominal infections due to susceptible organisms. It is active against both MSSA and MRSA, but clinical experience with its use in invasive infections is somewhat limited.50 The dose of tigecycline should be reduced in advanced cirrhosis. Adverse effects include nausea and vomiting.

Telavancin, dalbavancin, and oritavancin, investigational parenteral antibiotics that are derivatives of vancomycin, are in clinical trials. The pharmacokinetic activity of these agents is of interest: telavancin is being studied with a once-daily dosing interval and dalbavancin’s half-life allows once-weekly dosing. In a limited trial, dalbavancin was found to be safe and effective in the treatment of catheter-related bloodstream infections.51 None of the antibiotics in this group has been studied for treatment of S aureus endocarditis. Telavancin therapy has been associated with rash, hypokalemia, QT prolongation, and creatinine elevations. Gastrointestinal symptoms have been reported with the use of dalbavancin.

Ceftobiprole, another investigational agent, is the only cephalosporin antibiotic that is active against MRSA. It is given every 12 hours. Adverse effects include nausea and taste disturbance.

Iclaprim is a novel diaminopyrimidine and a dihydrofolate reductase inhibitor. In vitro, it is active against gram-positive bacteria, including MRSA, VISA, and VRSA; clinical investigations at this point are limited to the treatment of skin and soft-tissue infections.

Staphylococcus aureus is rearing its ugly head in new and interesting ways, both in the hospital and in the community.

Rates of invasive infections with methicillin-resistant S aureus (MRSA) have been increasing both in the hospital and in the community, a trend that has attracted considerable interest in the lay media. Curiously, the most common community-associated MRSA strain, which up to now has been distinct from hospital-associated MRSA strains, is invading our hospitals. Alarmingly, vancomycin (Vancocin), the drug of last resort for MRSA infections for the past 40 years, does not seem to be as effective as it used to be.

This paper summarizes the changing epidemiology of S aureus, particularly the emergence of MRSA outside of the hospital; reviews the difficulties associated with S aureus bacteremia and its treatment in view of; some changes in vancomycin susceptibility; and appraises the old and new treatment options.

MRSA IS ON THE RISE IN THE HOSPITAL

S aureus, a gram-positive, coagulase-positive bacterium, is one of the leading nosocomial bloodstream pathogens, second only to coagulase-negative staphylococci.1 And the incidence of S aureus infections is increasing. MRSA in particular is increasingly causing infections throughout hospitals, including intensive care units. As of 2004, nearly two-thirds of isolates of S aureus from intensive care units were MRSA.2

MRSA infections are worse than methicillin-susceptible S aureus (MSSA) infections in terms of the rates of death and other undesirable outcomes.3 Several factors may be responsible: MRSA infection may be a marker of severity of illness (sicker patients may be more likely to have MRSA), our treatment for MRSA may not be as effective as it is for MSSA, and the organism may be inherently more virulent.

METHICILLIN RESISTANCE IS ALSO ON THE RISE IN THE COMMUNITY

Community-associated MRSA began emerging clinically about 10 years ago. It was first described in a cohort of children with necrotizing pneumonia in Minnesota, but soon other populations at risk began to emerge, such as residents of correctional facilities, men who had sex with men, competitive athletes (eg, fencers, wrestlers, and football players), and Alaskan natives and other native populations. A common factor in all these groups was close proximity of the members to each other. Later, it began to spread beyond these traditional risk groups into the community at large.

Community-associated MRSA strains have a characteristic pattern of antimicrobial susceptibility (see below). In the laboratory, they grow somewhat faster than health-care-associated MRSA strains, but not as fast as MSSA. They have a strong association with skin and soft-tissue infections: when you see a skin or soft-tissue infection, be it in an outpatient or an inpatient, think about MRSA. Their virulence varies, but rapid onset and progression of illness are quite common. Their most common strain in the United States at present is USA 300.

Case 1: A young woman with necrotizing fasciitis

A 21-year-old college student presented to our service in May 2004 with high fever and severe arm pain, which had been worsening for several days. She had been previously healthy, had not had any contact with the health care system, and had not received any antibiotics.

Figure 1. Necrotizing fasciitis due to community-associated methicillin-resistant Staphylococcus aureus.
Her arm was red and extremely painful (Figure 1). Pain out of proportion to findings is a cardinal sign of necrotizing fasciitis, and this is indeed what she had.

Her blood cultures were positive for MRSA, as were cultures of the deep tissue of the deltoid muscle and fascia when she underwent emergency surgical debridement. The infection required several additional surgical debridements and removal of one head of her deltoid muscle, but she was fortunate: in the past, some patients with this problem might have undergone radical amputation of the arm or even more extensive surgery. This patient continued to have positive blood cultures 4 days postoperatively, but she ultimately recovered, completing 28 days of daptomycin (Cubicin) therapy at a dose of 6 mg/kg every 24 hours. The last 10 days of daptomycin therapy were given at home via a percutaneous intravenous central catheter.

Comment. The epidemiology of MRSA infections is changing. More patients who have no traditional risk factors, specifically health care contact, are getting MRSA infections. A recent report from the US Centers for Disease Control and Prevention (CDC) indicates that the proportion of patients with invasive disease due to MRSA has doubled since 2001–2002.4 Part of the reason undoubtedly is that MRSA, particularly community-associated MRSA, often carries specific virulence factors that make it more invasive. The CDC estimated that in 2005 there were nearly 100,000 cases of invasive MRSA infection in the United States, and nearly a fifth of these infections resulted in death.

 

 

Resistance and virulence factors in community-associated MRSA

Most community-associated MRSA strains carry a mobile genetic element called type IV SCCmec (staphylococcal chromosomal cassettemec) that enhances its antimicrobial resistance. This genetic component was probably borrowed from coagulase-negative staphylococci, in which it is quite common but does not cause as much of a problem. It is now present in a wide range of S aureus strains. Most of the S aureus strains that carry type IV SCCmec are MRSA, but a few MSSA strains do carry it as well.

The potent toxin Panton-Valentine leukocidin is an extracellular product that is detected in fewer than 5% of hospital strains but is more common in community-associated strains. It kills leukocytes by forming pores in the cell membrane and causing skin necrosis in cutaneous infections. It is associated with skin abscesses and rapidly progressive necrotizing pneumonia in MSSA or MRSA.

Epidemiologic differences between community- and health-care-associated MRSA

Patients with community-associated MRSA infections tend to be younger than those who traditionally get health-care-associated MRSA infections: in a study from Naimi et al in 2003, the mean ages were 23 vs 68 years.5 A greater proportion of patients with community-associated MRSA strains are nonwhite.4,5

Most community-associated MRSA infections are of the skin and soft tissue (75% in the series from Naimi et al5), but this pathogen causes other infections as well. Bacteremia of unknown origin has been seen, as has necrotizing pneumonia. Most of the skin and soft-tissue infections are relatively superficial, such as folliculitis or furunculosis, but deeper tissue infections such as necrotizing fasciitis and pyomyositis have also been seen.6

The incidence of community-associated MRSA infections varies greatly by geographic region.7 The northeastern United States has so far been relatively spared, but in Atlanta, Houston, and Los Angeles up to 80% of cases of characteristic skin or soft-tissue infections seen in emergency or outpatient departments are due to community-associated MRSA. Physicians at the Texas Children’s Hospital in Houston assume that all skin or soft-tissue infections are due to community-associated MRSA unless proven otherwise.8

Differences in antibiotic susceptibility

Community-associated MRSA is more susceptible to various antibiotics than health-care-associated MRSA,5 but not by much. Strains are usually susceptible to vancomycin, tetracyclines, trimethoprim-sulfamethoxazole (Bactrim, Septra), and rifampin (Rifadin). Unlike hospital strains, a fair number of community-acquired strains are susceptible to clindamycin (Cleocin) in the laboratory, but with a caveat: some of these clindamycin-susceptible strains actually may harbor the tools for inducible resistance. In fact, they can become resistant to clindamycin even without being exposed to it.

The laboratory test for inducible clindamycin resistance is called the D test. After coating an agar plate with S aureus, the technician places erythromycin and clindamycin disks. If the erythromycin induces clindamycin resistance, the plate is clear of growth around the clindamycin disk except for the portion nearest the erythromycin disk, leaving a characteristic D-shaped area of lucency.

Risk factors for MRSA

Moran et al7 analyzed the risk factors for community-associated MRSA in patients with skin or soft-tissue infections seen in the emergency department. The infection was more likely to be due to community-associated MRSA if the patient was black, had used any antibiotic in the past month, had a history of MRSA infection, or had close contact with a person with a similar infection. Many patients interpreted the infections as spider bites because the lesions tended to have a dark center surrounded by a tender area. These infections were not associated with underlying illness. In some cases, community-associated MRSA skin infections have been associated with tattooing and even manicuring.

However, it is very difficult to distinguish between community-associated MRSA and MSSA skin and soft-tissue infections on the basis of clinical and epidemiologic characteristics. Miller et al9 studied a large group of patients in Los Angeles who were hospitalized with community-associated skin and soft-tissue S aureus infections. All the patients were followed up for 30 days after hospital discharge. Regardless of whether they had MRSA or MSSA, they had similar outcomes. Close contacts of the patients also tended to develop infection.

A key point from this and many other studies: patients were more likely to remain infected if they did not undergo incision and drainage. This key intervention is indicated for any patient who has a skin and soft-tissue infection with an undrained focus of infection.

 

 

COMMUNITY-ASSOCIATED MRSA IS INVADING THE HOSPITAL

In a new development, community-associated MRSA strains are now appearing in the hospital. This is not only because patients are bacteremic when they come in: patients in the hospital are getting nosocomial infections due to community-associated MRSA strains.

Seybold et al10 analyzed 116 cases of MRSA bloodstream infections in Atlanta, GA. In 9 (8%) of the cases the patient had not had any contact with the health care system within the past year, and these cases were classified as truly community-associated. Of the remaining 107 cases, 49 (42%) were nosocomial, and the USA 300 strain—the predominant community-associated MRSA strain—accounted for 10 (20%) of the nosocomial cases.

In the recent CDC study of invasive MRSA infections, Klevens et al4 reported that nearly a third of cases of bacteremia were due to community-associated MRSA, and these strains accounted for a greater proportion of cases of cellulitis and endocarditis than did health-care-associated strains.

In a study of hospital-associated MRSA, Maree et al11 found that the percentage of cases in which the bacteria carried the SCCmec type IV marker had increased from less than 20% in 1999 to more than 50% in 2004.

Comment. Suffice it to say that we are surrounded by MRSA. Community-associated MRSA is here to stay. It is even invading our hospitals, and we need to consider this very carefully when choosing antimicrobial therapy.

NAGGING QUESTIONS ABOUT VANCOMYCIN

Case 2: Vancomycin-intermediate S aureus (VISA) bacteremia and endocarditis

In December 2006 we saw a very ill 60-year-old woman who was hospitalized with MRSA bacteremia, pacemaker endocarditis, and superior vena cava thrombosis. Although she was treated with vancomycin and rifampin, her condition worsened, she had a stroke, and she developed renal failure. In a difficult operation, the pacemaker was removed, but the bacteremia persisted. In early February 2007 she underwent another difficult operation in which the superior vena cava clot was debrided, a right atrial clot was removed, and her mitral valve was replaced. Less than 2 weeks later, and despite ongoing vancomycin and rifampin therapy, the MRSA bacteremia recurred.

During the approximately 6 weeks that the patient had been receiving these antibiotics, the minimal inhibitory concentration (MIC) of rifampin against the S aureus isolate increased from less than 1 μg/mL (susceptible) to 2 μg/mL (resistant). The MIC of vancomycin went from 2 μg/mL (susceptible) to 4 μg/mL (intermediately susceptible). Vancomycin and rifampin were discontinued, and daptomycin and gentamicin (Garamycin) therapy were started. (Her daptomycin MIC was 0.5 μg/mL). The patient’s condition stabilized, and she was discharged to a long-term nursing facility. She had no relapse of MRSA bacteremia, but she died in early April of that year.

Is vancomycin becoming less effective? Degrees of vancomycin resistance

Vancomycin has been our stalwart for treating MRSA infections for more than 40 years but it is not working as well as it used to, at least in certain situations.

Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:3040–3045
Figure 2. Population analysis of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate S aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-susceptible S aureus (VSSA). The population analysis shows how many cells in a fixed number of cells (usually about 107 colony-forming units [CFU]) of each strain are resistant to various concentrations of vancomycin. VRSA is a highly resistant and homogeneously resistant strain, with 100% of the population growing at each of the vancomycin concentrations tested. VISA is intermediately resistant, with 100% of the population growing at 4 μg of vancomycin per mL and also with significant subpopulations growing at 8 μg/mL. hVISA demonstrates heterogeneous resistance, having subpopulations of cells with various levels of resistance to vancomycin and including small populations of vancomycin-intermediate resistant cells with growth at 8 μg of vancomycin per mL.
Various terms describe the degrees of susceptibility or resistance to vancomycin (Figure 2).12

VRSA (vancomycin-resistant S aureus) is rare. These fully resistant strains probably acquired a resistance mechanism (the vanA operon) from vancomycin-resistant enterococci. Infections tend to occur in patients simultaneously infected with both S aureus and vancomycin-resistant enterococci, giving the bacteria an opportunity to exchange genetic material.

VISA (vancomycin-intermediate S aureus) infections tend to occur in patients like the one described above who have had long-term vancomycin therapy. VISA strains appear to overproduce a matrix that captures vancomycin and keeps it from entering the cell. On electron microscopy, these bacteria have a very thick cell wall.13

Vancomycin tolerance is a state in which the bacteria are “stunned” or kept in check but not killed by vancomycin. That is manifested in the laboratory by a ratio of minimum bactericidal concentration to MIC greater than 32.

hVISA (heteroresistant VISA) is new and worrisome. These organisms have an overall MIC in the susceptible range, but within that population are individual isolates with an MIC that is much higher—in the intermediate or perhaps even in the resistant range.14

Reported rates of hVISA vary from less than 2% to as high as 76%, because the methods for detecting it are still very poorly standardized. The usual automated laboratory tests do not detect hVISA.

hVISA is probably clinically relevant, as evidence is emerging both in vitro and in vivo that the higher the MIC for vancomycin, the worse the clinical outcome.15 hVISA has been associated with failures of therapy in several situations, usually in cases of severe invasive or deep infection, endocarditis, and bacteremia with vertebral osteomyelitis where vancomycin concentrations at the site of infection may be suboptimal.16–19 While most hVISA strains that have been described were resistant to methicillin, some were susceptible.

The E test is emerging as the standard test for hVISA. This test uses a plastic strip that contains gradually increasing concentrations of vancomycin along its length. Placed in the culture dish, the strip inhibits growth of the organism at its high-concentration end but not at its low-concentration end. If the sample contains hVISA, the cutoff is not well defined, with a few colonies growing at higher concentrations.

 

 

New definition of vancomycin susceptibility

Recognizing that the MICs for vancomycin have been rising in the last few years, the Clinical and Laboratory Standards Institute last year changed the break points between susceptibility and resistance. The new definitions are:

  • Susceptible—an MIC of 2.0 μg/mL or less (formerly 4.0 μg/mL or less)
  • Intermediate—4.0 to 8.0 μg/mL (formerly 8.0 to 16 μg/mL)
  • Resistant—16 μg/mL or greater (formerly 32 μg/mL or greater).

One should pay attention to the MIC numbers on the laboratory reports, not just to the words “susceptible” or “not susceptible.” If the number is, say, 0.5 μg/mL or less, the organism should really be susceptible. If the number is 1 or 2, it is still in the susceptible range, but those are the organisms that may cause problems later on.

Further, even if the vancomycin MIC is in the susceptible range, higher MICs may affect outcomes. The average duration of MRSA bacteremia on therapy is 8 to 9 days, vs 3 to 4 days with MSSA bacteremia.20,21 But Sakoulas et al15 found that, in MRSA bacteremia, the success rate with vancomycin therapy was 56% if the MIC was 0.5 or lower, compared with 10% if the MIC was 1.0 to 2.0 μg/mL. Examined in another way, the success rate was 50% if the logarithm of killing was 6.27 colony-forming units per mL or greater, 23% if 4.71 to 6.26, and zero if less than 4.71.

Case 3: Prolonged MRSA bacteremia

In the summer of 2006, a 66-year-old woman with a history of gastric bypass and cirrhosis underwent a long stay in the surgical intensive care unit because of a recurrent enterocutaneous fistula and chronic renal insufficiency. On November 5th, she had a positive blood culture for MRSA, which was treated appropriately with vancomycin for 4 weeks. She was discharged to subacute care but came back 2 days later, again with MRSA bacteremia. At that time her Hickman catheter, which had been inserted for total parenteral nutrition because of the enterocutaneous fistula, was removed.

Transthoracic echocardiography revealed no vegetations, but her bacteremia persisted. Her mental status was poor this entire time: she was mute and could barely be awakened. We looked for clots and infected clots; duplex ultrasonographic examinations of all four extremities were negative. Finally, magnetic resonance imaging of her back—performed empirically because of the persistent bacteremia—revealed vertebral osteomyelitis at level T12-L1. We also noticed on serial evaluations that the vancomycin MIC for her organism increased from 0.5 to 2.0 μg/mL, so therapy was changed from vancomycin to daptomycin.

Her bacteremia cleared. Follow-up echocardiography was negative, but she had two subsequent relapses of MRSA bacteremia, one in April 2007 and one before she died in the summer of 2007.

Prolonged bacteremia: Is it vancomycin resistance, or something else?

The MRSA isolates that cause prolonged bacteremia seem to have certain characteristics.22 Higher MICs are probably associated with longer periods of bacteremia. But some genetic components within some strains of S aureus give them a survival advantage. They have less susceptibility to the body’s thrombin-induced platelet microbicidal protein. These isolates are not only associated with prolonged bacteremia: they are also associated with osteomyelitis, deep abscesses, endocarditis, recurrent infection, and increased death rate.22 Clinical laboratories do not test for these genetic components. One wonders whether our patient may have had an isolate with these mutations that gave it a survival advantage.

Do not use vancomycin for MSSA

Avoid using vancomycin for MSSA infections. It has been shown time and time again that MSSA infections do not respond as well to vancomycin as they do to beta-lactam antibiotics, specifically to the semisynthetic penicillins such as oxacillin and nafcillin, and even some of the first-generation cephalosporins. Chang et al23 found that patients with MSSA bacteremia had higher rates of persistent infections, relapse, and bacteriologic failure if they received vancomycin than if they received nafcillin.

Do vancomycin trough levels affect toxicity?

The vancomycin trough levels that we aimed for in the past (5 to 10 μg/mL) were probably too low. Today, we aim for trough levels of 15 to 20 μg/mL, and many physicians are aiming for 20 to 25 μg/mL. Part of the reason is that vancomycin MICs are higher than they used to be: in order to keep the vancomycin level above the MIC for a longer period of time, the vancomycin trough level needs to be higher. In theory, keeping the vancomycin levels above the MIC for longer periods should improve outcomes. Yet Fowler et al22 found that vancomycin trough levels among patients who had persistent MRSA bacteremia were actually higher than trough levels among those in whom the bacteremia resolved, although the difference was not statistically significant.

We measure the vancomycin trough level to make sure it is high enough (and give larger doses if it is not); among adults, peak levels need not be monitored on a routine basis because of the predictable pharmacokinetics of vancomycin.

Vancomycin toxicity can be either idiosyncratic or synergistic. Idiosyncratic toxicity occurs when a patient who has been on vancomycin for a long time develops a fixed rash, not associated with infusion. This is an immunologic phenomenon. It is a rare and very serious situation and may require steroid therapy.

Synergistic toxicity occurs when vancomycin is given with other nephrotoxic agents, notably gentamicin. Vancomycin plus gentamicin equals nephrotoxicity. Vancomycin alone is usually not nephrotoxic, but close monitoring of renal function parameters is warranted with the use of higher doses.24

 

 

IN UNEXPLAINED BACTEREMIA, LOOK FOR ENDOCARDITIS

In blood cultures from patients with bacteremia, S aureus is never a contaminant. Even if just one blood culture is positive for S aureus, believe that S aureus is the culprit.

Reports in the 1950s suggested that at least half of patients who had S aureus bacteremia had endocarditis,25 leading to recommendations that all patients with S aureus bacteremia without an obvious primary source of infection should be evaluated for endocarditis. Subsequent estimates were lower, in the range of 15% to 25%.26,27 However, throughout the world S aureus endocarditis continues to have a very high mortality rate: at least a third of patients die.28

Clinical criteria (community acquisition, no primary focus, and metastatic sequelae) were developed to try to predict the risk of endocarditis in bacteremic patients.26 However, these criteria did not work very well. The clinical definition of endocarditis has evolved. The criteria of von Reyn et al29 from 1981 did not use echocardiography as part of the definition, but the 1994 Duke criteria,30 which were refined31 in 2000, use both clinical and echocardiographic parameters.

Stratton et al32 performed transthoracic echocardiography in 14 patients with bacteremia and found 1 patient with cryptic tricuspid infective endocarditis. Bayer et al33 subsequently reported that of 72 patients with bacteremia, 6 (18%) of those who had no clinical findings suggestive of infectious endocarditis had findings on echocardiography that led to changes in their regimen. Adding echocardiography to three clinical risk factors increased the sensitivity of diagnosing endocarditis from 70% to 85% with a specificity of 100% and predictive value of 96%.

The Duke criteria call for transesophageal echocardiography, which is not feasible in some patients, eg, those with cirrhosis and esophageal varices.

S aureus endocarditis has changed over the years as our patient population has changed, and MRSA endocarditis tends to hit some of our most vulnerable patients. In a study by Miro et al34 in 2005, MRSA was the leading pathogen in patients who were diagnosed with S aureus endocarditis in 1990 or later. We will only see these numbers go up. Patients with diabetes tend to have more MRSA, and of diabetic patients with MRSA endocarditis, 30% to 40% die in the hospital.

Indications for surgery

Certain conditions are indications for surgery among patients with endocarditis, and no antibiotic will cure the endocarditis if the patient has one of these conditions, eg:

  • Persistent bacteremia during antibiotic therapy
  • Recurrent emboli
  • Heart failure that cannot be controlled
  • Perivalvular or myocardial abscesses
  • Large vegetations
  • Early prosthetic valve infection
  • Certain arrhythmias.

How long should S aureus bacteremia be treated?

In cases of bacteremia in which endocarditis has been ruled out and removable foci of infection (eg, intravascular catheters) have been removed, some evidence indicates that treatment for 2 weeks would be as effective as the 4 to 6 weeks that we would use for endocarditis or other severe or invasive infections.35 The issue is controversial. If the patient has had frequent hospitalizations or a chronic medical condition I would hesitate to treat for less than 4 weeks, even if the infection appears to be associated with a removable focus.

Treatment of endocarditis

In the guidelines for treatment of endocarditis from the American Heart Association and Infectious Diseases Society of America,36 all the recommendations are relatively old and many of them are somewhat empiric—they are not based on evidence from randomized clinical trials. Rather, they are best opinions based on clinical experience and some observational studies over the years.

For MSSA. In cases of native-valve endocarditis, oxacillin (Bactocill), nafcillin (Unipen), or another semisynthetic beta-lactam antibiotic is recommended. For penicillin-allergic patients, we have other options, such as cefazolin (Ancef, Kefzol).

Combination therapy is frequently recommended for native valve endocarditis as well as for prosthetic valve endocarditis, with either rifampin or gentamicin along with a primary agent. There is some evidence that one can clear staphylococcal bacteremia a day or two more quickly by use of combination therapy with nafcillin plus an aminoglycoside than with nafcillin alone.37,38 For MSSA-associated endocarditis, vancomycin does not work as well as beta-lactam antibiotics.39,40

Korzeniowski and Sande37 and Chambers et al38 reported that the mean duration of bacteremia was 3.4 days for patients treated with nafcillin alone and 2.9 days for those treated with nafcillin plus an aminoglycoside. These studies led to consideration of a short course of gentamicin to clear the bacteremia quickly.

With MRSA, bacteremia often requires a week or more to clear. Levine et al21 reported a study in 42 patients, mostly injection-drug users, with right-sided native-valve endocarditis. The median duration of bacteremia was 7 days in patients who received vancomycin alone vs 9 days in those who received vancomycin plus rifampin; however, some patients were bacteremic for up to 27 days. Fever persisted for a median of 7 days, probably partly due to septic pulmonary emboli. Three patients died, and three required valve replacement.

 

 

NEW ANTIBIOTICS

Several new antibiotics are active against gram-positive cocci.41–44 However, the majority of them have not been prospectively studied for treating bacteremia or endocarditis.

Quinupristin/dalfopristin (Synercid) has not been formally studied for treatment of MRSA bacteremia or endocarditis. There are a few case reports of its use in these conditions.45 Quinupristin/dalfopristin is bacteriostatic, and its use may be associated with phlebitis, myalgias, and arthralgias.46

Linezolid (Zyvox) is approved for treatment of complicated skin and soft-tissue infections and for hospital-acquired pneumonia. There have been no specific studies of linezolid in the treatment of S aureus bacteremia or endocarditis. However, Shorr et al47 retrospectively looked at the bacteremic patients in five previous studies of linezolid vs vancomycin and found 144 cases of S aureus bacteremia, half of which were due to MRSA. Of 53 assessable patients with MRSA bacteremia, the primary infection was cured in 14 (56%) of the linezolid patients and 13 (46%) of the vancomycin patients.

The oral form is 100% bioavailable. One should avoid concomitant use of serotonin-reuptake inhibitors because of the risk of serotonin syndrome. Adverse effects include altered taste sensation and peripheral neuropathy. There are other potential toxicities, including hematologic changes (thrombocytopenia, leukopenia) and metabolic effects (lactic acidosis), so clinical and laboratory monitoring is important.48 The role of linezolid in the treatment of patients with S aureus bacteremia or endocarditis remains to be defined.

Daptomycin is indicated for complicated skin and soft-tissue infections, bacteremia, and right-sided endocarditis due to S aureus. Fowler et al20 found that daptomycin was not inferior to beta-lactam antibiotics for treatment of MSSA bacteremia and right-sided endocarditis, and for MRSA infections it outperformed vancomycin, but the difference was not statistically significant.

The dosing interval should be increased from once every 24 hours to every 48 hours if the creatinine clearance is 30 mL/minute or less. Adverse effects include myalgia, rhabdomyolysis (rare), and elevations in creatine phosphokinase. Reports of rising MICs during daptomycin therapy, in some cases associated with persistent infection,49 suggest that careful attention be paid to dosing and clinical monitoring.

Tigecycline (Tygacil) is indicated for complicated skin and soft-tissue infections and complicated intra-abdominal infections due to susceptible organisms. It is active against both MSSA and MRSA, but clinical experience with its use in invasive infections is somewhat limited.50 The dose of tigecycline should be reduced in advanced cirrhosis. Adverse effects include nausea and vomiting.

Telavancin, dalbavancin, and oritavancin, investigational parenteral antibiotics that are derivatives of vancomycin, are in clinical trials. The pharmacokinetic activity of these agents is of interest: telavancin is being studied with a once-daily dosing interval and dalbavancin’s half-life allows once-weekly dosing. In a limited trial, dalbavancin was found to be safe and effective in the treatment of catheter-related bloodstream infections.51 None of the antibiotics in this group has been studied for treatment of S aureus endocarditis. Telavancin therapy has been associated with rash, hypokalemia, QT prolongation, and creatinine elevations. Gastrointestinal symptoms have been reported with the use of dalbavancin.

Ceftobiprole, another investigational agent, is the only cephalosporin antibiotic that is active against MRSA. It is given every 12 hours. Adverse effects include nausea and taste disturbance.

Iclaprim is a novel diaminopyrimidine and a dihydrofolate reductase inhibitor. In vitro, it is active against gram-positive bacteria, including MRSA, VISA, and VRSA; clinical investigations at this point are limited to the treatment of skin and soft-tissue infections.

References
  1. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39:309371. Erratum in: Clin Infect Dis 2004; 39:1093.
  2. US Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance (NNIS) System. Campaign to prevent antimicrobial resistance. www.cdc.gov/drugresistance/healthcare/ha/HASlideSet.ppt.
  3. Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med 2002; 162:22292235.
  4. Klevens RM, Morrison MA, Nadle J, et al; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:17631771.
  5. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290:29762984.
  6. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352:14451453.
  7. Moran GJ, Krishnadasan A, Gorwitz RJ, et al EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666674.
  8. Mishaan AM, Mason EO, Martinez-Aquilar G, et al. Emergence of a predominant clone of community-acquired Staphylococcus aureus among children in Houston, Texas. Pediatr Infect Dis J 2005; 24:201206.
  9. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S. aureus infection: a prospective investigation. Clin Infect Dis 2007; 44:471482.
  10. Seybold U, Kourbatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis 2006; 42:647656.
  11. Maree CL, Daum RS, Boyle-Vavra S, Matayoshi K, Miller LG. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerg Infect Dis 2007; 13:236242.
  12. Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:30403045.
  13. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999; 340:517523.
  14. Schwaber MJ, Wright SB, Carmeli Y, et al. Clinical implications of varying degrees of vancomycin susceptibility in methicillin-resistant Staphylococcus aureus bacteremia. Emerg Infect Dis 2003; 9:657–664. Erratum in: Emerg Infect Dis 2004; 10:160.
  15. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004; 42:23982402.
  16. Naimi TS, Anderson D, O’Boyle C, et al. Vancomycin-intermediate Staphylococcus aureus with phenotypic susceptibility to methicillin in a patient with recurrent bacteremia. Clin Infect Dis 2003; 36:16091612.
  17. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother 2003; 47:12621266.
  18. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogenous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004; 38:448451.
  19. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521528.
  20. Fowler VG, Boucher HW, Corey GR, et al. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653665.
  21. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115:674680.
  22. Fowler VG, Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004; 190:11401149.
  23. Chang FY, Peacock JE, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore) 2003; 82:333339.
  24. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006; 166:21382144.
  25. Wilson R, Hamburger M. Fifteen years’ experience with staphylococcus septicemia in a large city hospital; analysis of fifty-five cases in the Cincinnati General Hospital 1940 to 1954. Am J Med 1957; 22:437457.
  26. Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med 1976; 60:495500.
  27. Shah M, Watanakunakorn C. Changing patterns of Staphylococcus aureus bacteremia. Am J Med Sci 1979; 278:115121.
  28. Fowler VG, Miro JM, Hoen B, et al ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293:30123021. Erratum in: JAMA 2005; 294:900.
  29. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: an analysis based on strict case definition. Ann Intern Med 1981; 94:505518.
  30. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200209.
  31. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633638.
  32. Stratton JR, Werner JA, Pearlman AS, Janko CL, Kliman S, Jackson MC. Bacteremia and the heart. Serial echocardiographic findings in 80 patients with documented or suspected bacteremia. Am J Med 1982; 73:851858.
  33. Bayer AS, Lam K, Ginzton L, Normal DC, Chiu CY, Ward JI. Staphylococcus aureus bacteremia. Clinical, serologic, and echocardiographic findings in patients with and without endocarditis. Arch Intern Med 1987; 147:457462.
  34. Miro JM, Anguera I, Cabell CH, et al International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database. Clin Infect Dis 2005; 41:507–514. Erratum in: Clin Infect Dis 2005; 41:10751077.
  35. Jernigan JA, Farr BM. Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis. Ann Intern Med 1993; 119:304311.
  36. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394e434. Erratum in: Circulation 2005; 112:2373. Circulation 2007; 115:e408.
  37. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982; 97:496503.
  38. Chambers HF, Korzeniowski OM, Sande MA. Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts. Medicine (Baltimore) 1983; 62:170177.
  39. Gentry CA, Rodvold KA, Novak RM, Hershow RC, Naderer OJ. Retrospective evaluation of therapies for Staphylococcus aureus endocarditis. Pharmacotherapy 1997; 17:990997.
  40. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34:12271231.
  41. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003; 36:473481.
  42. Rybak MJ. Therapeutic options for Gram-positive infections. J Hosp Infect 2001; 49 suppl A:S25S32.
  43. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2007; 45 suppl 3:S184S190.
  44. Appelbaum PC, Jacobs MR. Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria. Curr Opin Microbiol 2005; 8:510517.
  45. Drew RH, Perfect JR, Srinath L, Kirkimilis E, Dowzicky M, Talbot GH for the Synercid Emergency-Use Study Group. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. J Antimicrob Chemother 2000; 46:775784.
  46. Lamb HM, Figgitt DP, Faulds D. Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections. Drugs 1999; 58:10611097.
  47. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother 2005; 56:923929.
  48. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50:15991602.
  49. Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007; 45:601608.
  50. Munoz-Price LS, Lolans K, Quinn JP. Four cases of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections treated with tigecycline. Scand J Infect Dis 2006; 38:10811084.
  51. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis 2005; 40:37480.
References
  1. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39:309371. Erratum in: Clin Infect Dis 2004; 39:1093.
  2. US Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance (NNIS) System. Campaign to prevent antimicrobial resistance. www.cdc.gov/drugresistance/healthcare/ha/HASlideSet.ppt.
  3. Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med 2002; 162:22292235.
  4. Klevens RM, Morrison MA, Nadle J, et al; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:17631771.
  5. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290:29762984.
  6. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352:14451453.
  7. Moran GJ, Krishnadasan A, Gorwitz RJ, et al EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666674.
  8. Mishaan AM, Mason EO, Martinez-Aquilar G, et al. Emergence of a predominant clone of community-acquired Staphylococcus aureus among children in Houston, Texas. Pediatr Infect Dis J 2005; 24:201206.
  9. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S. aureus infection: a prospective investigation. Clin Infect Dis 2007; 44:471482.
  10. Seybold U, Kourbatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis 2006; 42:647656.
  11. Maree CL, Daum RS, Boyle-Vavra S, Matayoshi K, Miller LG. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerg Infect Dis 2007; 13:236242.
  12. Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother 2003; 47:30403045.
  13. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999; 340:517523.
  14. Schwaber MJ, Wright SB, Carmeli Y, et al. Clinical implications of varying degrees of vancomycin susceptibility in methicillin-resistant Staphylococcus aureus bacteremia. Emerg Infect Dis 2003; 9:657–664. Erratum in: Emerg Infect Dis 2004; 10:160.
  15. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004; 42:23982402.
  16. Naimi TS, Anderson D, O’Boyle C, et al. Vancomycin-intermediate Staphylococcus aureus with phenotypic susceptibility to methicillin in a patient with recurrent bacteremia. Clin Infect Dis 2003; 36:16091612.
  17. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother 2003; 47:12621266.
  18. Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogenous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004; 38:448451.
  19. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521528.
  20. Fowler VG, Boucher HW, Corey GR, et al. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653665.
  21. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115:674680.
  22. Fowler VG, Sakoulas G, McIntyre LM, et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004; 190:11401149.
  23. Chang FY, Peacock JE, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore) 2003; 82:333339.
  24. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006; 166:21382144.
  25. Wilson R, Hamburger M. Fifteen years’ experience with staphylococcus septicemia in a large city hospital; analysis of fifty-five cases in the Cincinnati General Hospital 1940 to 1954. Am J Med 1957; 22:437457.
  26. Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med 1976; 60:495500.
  27. Shah M, Watanakunakorn C. Changing patterns of Staphylococcus aureus bacteremia. Am J Med Sci 1979; 278:115121.
  28. Fowler VG, Miro JM, Hoen B, et al ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293:30123021. Erratum in: JAMA 2005; 294:900.
  29. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: an analysis based on strict case definition. Ann Intern Med 1981; 94:505518.
  30. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200209.
  31. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633638.
  32. Stratton JR, Werner JA, Pearlman AS, Janko CL, Kliman S, Jackson MC. Bacteremia and the heart. Serial echocardiographic findings in 80 patients with documented or suspected bacteremia. Am J Med 1982; 73:851858.
  33. Bayer AS, Lam K, Ginzton L, Normal DC, Chiu CY, Ward JI. Staphylococcus aureus bacteremia. Clinical, serologic, and echocardiographic findings in patients with and without endocarditis. Arch Intern Med 1987; 147:457462.
  34. Miro JM, Anguera I, Cabell CH, et al International Collaboration on Endocarditis Merged Database Study Group. Staphylococcus aureus native valve infective endocarditis: report of 566 episodes from the International Collaboration on Endocarditis Merged Database. Clin Infect Dis 2005; 41:507–514. Erratum in: Clin Infect Dis 2005; 41:10751077.
  35. Jernigan JA, Farr BM. Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis. Ann Intern Med 1993; 119:304311.
  36. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394e434. Erratum in: Circulation 2005; 112:2373. Circulation 2007; 115:e408.
  37. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982; 97:496503.
  38. Chambers HF, Korzeniowski OM, Sande MA. Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts. Medicine (Baltimore) 1983; 62:170177.
  39. Gentry CA, Rodvold KA, Novak RM, Hershow RC, Naderer OJ. Retrospective evaluation of therapies for Staphylococcus aureus endocarditis. Pharmacotherapy 1997; 17:990997.
  40. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34:12271231.
  41. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003; 36:473481.
  42. Rybak MJ. Therapeutic options for Gram-positive infections. J Hosp Infect 2001; 49 suppl A:S25S32.
  43. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2007; 45 suppl 3:S184S190.
  44. Appelbaum PC, Jacobs MR. Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria. Curr Opin Microbiol 2005; 8:510517.
  45. Drew RH, Perfect JR, Srinath L, Kirkimilis E, Dowzicky M, Talbot GH for the Synercid Emergency-Use Study Group. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. J Antimicrob Chemother 2000; 46:775784.
  46. Lamb HM, Figgitt DP, Faulds D. Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections. Drugs 1999; 58:10611097.
  47. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother 2005; 56:923929.
  48. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50:15991602.
  49. Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007; 45:601608.
  50. Munoz-Price LS, Lolans K, Quinn JP. Four cases of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections treated with tigecycline. Scand J Infect Dis 2006; 38:10811084.
  51. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis 2005; 40:37480.
Issue
Cleveland Clinic Journal of Medicine - 75(3)
Issue
Cleveland Clinic Journal of Medicine - 75(3)
Page Number
177-180, 183-186, 190-192
Page Number
177-180, 183-186, 190-192
Publications
Publications
Topics
Article Type
Display Headline
Staphylococcus aureus: The new adventures of a legendary pathogen
Display Headline
Staphylococcus aureus: The new adventures of a legendary pathogen
Sections
Inside the Article

KEY POINTS

  • Community-associated MRSA infections tend to affect patients younger than those who traditionally get hospital-associated MRSA infections. Most of these infections are of the skin and soft tissues, but this pathogen can also affect deeper tissues, and bacteremia and necrotizing pneumonia have been reported.
  • For patients with skin and soft-tissue infections due to MRSA, incision and drainage rather than antibiotic therapy is often the key intervention.
  • Vancomycin has been our stalwart for treating MRSA infections for more than 40 years, but it is not working as well as it used to, at least in certain situations. Vancomycin should not be used to treat infections due to methicillin-susceptible S aureus.
  • Needed are better understanding of the factors that influence persistent S aureus bacteremia, well-controlled, prospective studies, and continued antibiotic development.
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

Preventing and managing diabetic complications in elderly patients

Article Type
Changed
Tue, 05/03/2022 - 16:05
Display Headline
Preventing and managing diabetic complications in elderly patients

In elderly patients, as in all patients, diabetes is much more than the blood glucose level. However, in elderly patients the disease accelerates other common conditions of that population and markedly complicates their management.

Hypertension, coronary artery disease, and cerebrovascular attacks are more common in patients with diabetes.1 Longitudinal studies of elderly and middle-aged people with diabetes show increased rates of cognitive decline and dementia.2–4 Depression, urinary incontinence, and falls are also more common in elderly patients with diabetes. Physical disability is also increased: women with diabetes are half as likely to be able to manage ordinary physical tasks such as walking, climbing stairs, and doing housework as women without diabetes.5

In an earlier paper in this journal,6 we reviewed the management of diabetes per se in elderly patients. In the pages that follow, we review the management of its associated conditions.

HEART RISK TRUMPS BLOOD SUGAR

Coronary artery disease is by far the leading cause of death in elderly people with diabetes: 40% to 50% of patients with type 2 diabetes die of cardiac disease.7–9 The conventional risk factors—hypertension, hyperlipidemia, smoking, and diabetes—remain risk factors throughout old age. Risk reduction should focus on treating hypertension and dyslipidemia, smoking cessation, aspirin therapy, and exercise. While glycemic control reduces the risk of microvascular complications (eg, diabetic retinopathy and nephropathy) after about 8 years of treatment, benefits from control of elevated blood pressure and cholesterol occur after only 2 to 3 years.

Tight control of hypertension confers significant benefit

The United Kingdom Prospective Diabetes Study (UKPDS)10 found that patients who had tight control of blood pressure (mean treated blood pressure 144/82 mm Hg) had 24% fewer diabetes-related end points, 32% fewer diabetes-related deaths, 44% fewer strokes, a 34% reduced risk of deterioration of retinopathy, and a 47% reduced risk of visual deterioration than patients who had usual control (mean treated blood pressure 157/87 mm Hg). The benefit of treating hypertension outweighed the benefits of tight glycemic control.

A strong focus on blood pressure control should be a major focus of any treatment program. The American Geriatrics Society goal for blood pressure is less than 140/80 mm Hg if tolerated. Others have proposed more stringent targets.

Lipid control

Lipid control is integral to managing elderly patients with diabetes. In the Cholesterol and Recurrent Events trial11 and the Heart Protection Study,12 the cardiovascular benefits of reducing serum low-density lipoprotein cholesterol (LDL-C) levels were similar in elderly and younger patients with diabetes. In a meta-analysis of secondary prevention trials, absolute risk reduction was greatest in subjects older than 65 years with either diabetes or diastolic hypertension.

The American Diabetes Association,13 the American Geriatrics Society,14 and the Department of Veterans Affairs15,16 have all set a goal for serum LDL-C of less than 100 mg/dL. In addition, the American Diabetes Association has set goal levels for triglycerides (< 150 mg/dL) and high-density lipoprotein cholesterol (> 40 mg/dL).

Glycemic control

The importance of tight glycemic control in preventing coronary heart disease in the elderly is somewhat controversial. Treatment guidelines for elderly patients with diabetes are mainly extrapolated from the UKPDS, in which patients were a mean of 54 years old at the start of the study. After 10 years, the mean hemoglobin A1c levels were 7.9% in patients receiving conventional control and 7.0% in patients with intensive therapy. Every 1% reduction in hemoglobin A1c was associated with a 37% decline in microvascular complications of diabetes, a 14% decline in myocardial infarctions, and a 21% decline in any diabetes-related outcome.17

In the original trial,18 the rate of myocardial infarction was 17.4% in the conventional treatment group vs 14.7% in the intensive group (P = .052), and the risk of stroke did not differ. No thresholds for realizing benefits from reducing fasting glucose or hemoglobin A1c levels were detected.

A recent cohort study involving about 10,000 participants aged 45 to 79 years found that the risk of cardiovascular disease and death from any cause increased continuously with increasing hemoglobin A1c levels in people with or without diabetes.19 However, the impact of treatment remains to be clarified. The Action to Control Cardiovascular Risk in Diabetes trial will address this question (and others), but results will not be available for several years.

 

 

RETINOPATHY IS A MAJOR CAUSE OF BLINDNESS

Diabetic retinopathy, a leading cause of blindness in the United States, is perhaps the most threatening of the chronic microvascular complications of diabetes for elderly patients. The strongest predictor of retinopathy is the duration of diabetes.20–22 Retinopathy is classified as being nonproliferative, preproliferative, or proliferative.

Ischemia is believed to be the major cause of diabetic retinopathy, and glucose control has been shown to be of major benefit. A study of young adults with type 1 diabetes found that intensive therapy reduced the risk of developing retinopathy by 76% and slowed the progression of retinopathy by 54%. Comparable data for patients with type 2 diabetes are lacking.

Of some concern is a study in which retinopathy progressed more rapidly during the first year of aggressive insulin therapy in elderly patients with diabetes and baseline retinopathy.23 Further research is needed to identify which subgroups would benefit most from aggressive glycemic control.

In addition to specific ophthalmologic treatment, managing cardiovascular risk factors may reduce the progression of retinopathy: each cardiovascular risk factor has been found to also be a risk factor for retinopathy. Hypertension is an independent risk factor for any retinopathy, and its tight control reduces progression.20,24 Aspirin therapy has not been found to confer either risk or benefit.25,26

Although guidelines typically call for yearly ophthalmic examinations to screen for retinopathy, whether this is cost-effective has been questioned.27,28 But people older than 65 years with diabetes also have twice the risk of developing cataracts and three times the risk of developing glaucoma than those without diabetes. Considering the effects of visual loss on quality of life as well as the subsequent higher risk of accidents, eye examinations by an ophthalmologist at the time of diagnosis and annually thereafter are recommended. Tight glycemic and blood pressure control remains the cornerstone in the primary prevention of diabetic retinopathy. Panretinal and focal retinal laser photocoagulation reduces the risk of visual loss in patients with severe retinopathy and macular edema, respectively.29

NEUROPATHY PRESENTS IN MANY FORMS

Neuropathy is a particularly distressing complication and can lead to loss of sleep, limitation of activity, and depression.26,30,31 Diabetic neuropathies include focal neuropathies (entrapment syndromes and mono-neuropathies), polyneuropathy, and autonomic neuropathy.

Distal symmetric polyneuropathy (“glove and stocking” sensory symptoms) is the most common neuropathy of elderly people with diabetes. Pain, which can interrupt sleep and limit activity, can be treated with the anticonvulsants gabapentin (Gabarone, Neurontin), phenytoin (Dilantin, Phenytek) and carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), and with tricyclic antidepressants. However, the anticholinergic effects of tricyclic antidepressants limit their use in older patients. Newer agents, such as duloxetine (Cymbalta) and pregabalin (Lyrica) show promise.30,31 Dysesthesia of a burning quality is sometimes treated with topical capsaicin or with oral mexiletine (Mexitil), although their role in treating older patients is not well established.

Patients with distal sensory polyneuropathy are predisposed to develop Charcot joints, which may mimic gout or degenerative joint disease. Plain radiography of the foot can help differentiate these diseases. Distal sensory polyneuropathy also predisposes patients to neuropathic foot ulcer, the leading cause of foot amputation in the United States.32

Feet should be inspected at each office visit. Testing sensation with a monofilament detects sensory neuropathy. Patients should be encouraged to examine their feet daily. Therapeutic shoes, prescribed by a podiatrist and individually designed to prevent blisters, calluses, and ulcers, are covered by Medicare for peripheral neuropathy if any of the following are also present: callus formation, poor circulation, foot deformity, or a history of foot callus, ulcer, or amputation (partial or complete). Medicare will pay for one pair of shoes plus three pairs of inserts per year.

Proximal motor neuropathy (diabetic amyotrophy) primarily affects elderly patients. It begins with unilateral thigh pain, which becomes bilateral and progresses to proximal muscle weakness and wasting. Distal symmetric polyneuropathy may also be present. Treatment includes glycemic control (usually with insulin) and physical therapy. Some forms of amyotrophy respond to immunotherapy.

Autonomic neuropathy, although not painful, can be the most life-threatening form of diabetic neuropathy.33 Tachycardia increases the risk of sudden death, while postural hypotension increases the risk of syncope, falling, and injury. Other forms of autonomic neuropathy include neurogenic bladder, sexual dysfunction, gastropathy (which is particularly sensitive to glycemic control), enteropathy, and gustatory sweating. Patients with autonomic neuropathy are more likely to have hypoglycemic unawareness.

 

 

NEPHROPATHY CAN PROGRESS RAPIDLY

Elderly patients with diabetes are especially at risk of developing nephropathy, which progresses from microalbuminuria to overt proteinuria to renal insufficiency and end-stage renal disease. Nephropathy may develop over a shorter time than the typical 10 to 20 years in younger patients. Independent risk factors for proteinuria and renal insufficiency include poor glycemic control over many years, hypertension, longer duration of diabetes, male sex, high serum total cholesterol levels, and smoking. Elderly patients are also at risk of renal insults such as receiving intravenous iodinated contrast agents in the course of radiologic procedures, nephrotoxic drugs, and comorbid illness such as congestive heart failure.

The diagnosis of diabetic nephropathy is usually made clinically and not by renal biopsy. Diabetic nephropathy can be diagnosed with almost 100% specificity in type 1 diabetes and more than 85% specificity in type 2 diabetes by a urinary albumin excretion of more than 300 mg per day and an appropriate time course in the absence of other obvious causes of renal disease. The urinary albumin-to-creatinine ratio can be used to screen for microalbuminuria (the precursor of frank proteinuria and renal insufficiency). A value of more than 30 mg of albumin per gram of creatinine suggests that albumin excretion exceeds 30 mg and that microalbuminuria is present.

Prevention is a cornerstone of management. Good glycemic control reduces the risk of microalbuminuria, the progression of albuminuria, and the development of renal insufficiency. Lowering blood pressure reduces the decline in glomerular filtration rate and albuminuria. Angiotensin-converting enzyme (ACE) inhibitors reduce the rate of progression of proteinuria and reduce the rate of end-stage renal disease, although the data are stronger in patients with type 1 diabetes.34 When side effects such as cough limit the use of ACE inhibitors, angiotensin receptor blockers can be used as an alternative. Blood pressure should be controlled to reduce stroke and cardiovascular complications, regardless of whether microalbuminuria is present.35

End-stage renal disease in elderly patients with diabetes is becoming increasingly frequent. Nephropathy in older patients is different from that in younger patients. In elderly patients, the pathologic findings may suggest ischemia and hypertension, and the classic Kimmelstiel-Wilson lesions may be absent. Patients may present with end-stage renal disease following an episode of acute renal failure that does not resolve, which may occur after a radiologic procedure involving an iodinated contrast agent.

NONKETOTIC HYPEROSMOLAR COMA

Nonketotic hyperosmolar coma occurs predominantly in elderly patients with type 2 diabetes. Predisposing factors include dementia, infection, stroke, and myocardial infarction. Coma results from osmotic diuresis due to hyperglycemia and consequent dehydration. A drop in the glomerular filtration rate promotes further hyperglycemia and dehydration in a vicious circle. Glucose levels commonly reach 600 mg/dL or more, and serum osmolality often exceeds 320 mOsm/L. A fluid deficit of 5 to 10 L is typical.

Fluid replacement is the mainstay of treatment. Because free water is typically lost in an osmotic diuresis, 0.9% (normal) saline is usually given if hemodynamic instability is present or 0.45% (half-normal) saline otherwise. Insulin is also required, as is specific treatment of the precipitating cause, eg, infection. Ketoacidosis may also occur in the elderly.

Recovery from coma or improvement in mental status may lag behind correction of the serum osmolality and may take several days. Mortality rates can be high: severe hyperosmolarity, advanced age, and nursing home residence are the major risk factors for death.

INFECTIONS: SEVERE AND UNUSUAL

Elderly patients with diabetes are at increased risk of developing severe and unusual infections, particularly malignant external otitis. Necrotizing Pseudomonas aeruginosa infection initially involves the external ear canal and progresses to the mastoid air cells, the skull base, or temporal bone. The clinical presentation consists of fever, otalgia, otorrhea, and less commonly, cranial nerve palsy. Treatment involves surgical debridement and antibiotics.

Other infections associated with diabetes include rhinocerebral mucormycosis, necrotizing fasciitis, emphysematous cholecystitis, and emphysematous pyelonephritis. An elderly patient with diabetes is also at increased risk of renal papillary necrosis, which presents as insidious renal failure.

COGNITIVE IMPAIRMENT

Elderly people with diabetes are at increased risk of cognitive impairment, which poses a barrier to taking medications appropriately and performing other tasks of self-management.

Because dementia may go undetected, particularly in the early stages, cognitive function should be assessed in elderly patients when they fail to take therapy correctly or have frequent episodes of hypoglycemia, or if glycemic control deteriorates without an obvious explanation. Caregivers play a critical role in detecting and reporting early cognitive impairment.

DEPRESSION IS OFTEN UNDETECTED

Elderly patients with diabetes have a higher rate of depression than do age-matched controls, but it is commonly underdetected and undertreated.5,36 Depression has been associated with poor glycemic control, and treatment of depression is associated with improved control. Routine screening for depression should be performed; a variety of diagnostic instruments are available. Particular attention should be given to medications that are associated with depression.

 

 

POLYPHARMACY

Many elderly patients take multiple medications. Polypharmacy increases the risk of drug side effects, interactions, and nonadherence to taking medications.37–39 This problem is increased in diabetes, in which several medications are necessary to manage hyper-glycemia, hyperlipidemia, hypertension, and other associated conditions.

Patients should keep accurate medication lists, including over-the-counter medications, herbs, and nutritional supplements. Physicians should carefully review each medication to check if it is appropriate and used correctly.

FALLS

Elderly patients with diabetes mellitus are at increased risk of injurious falls, which are associated with high rates of complications, death, and functional decline.40,41 Risk factors include frailty and functional disability, visual impairment, peripheral or autonomic neuropathy, hypoglycemia, and polypharmacy.

Elderly patients should be screened for their risk of falls, and appropriate measures should be instituted. The American Geriatrics Society has guidelines for preventing falls in the elderly.41

URINARY INCONTINENCE

Elderly women with diabetes are at increased risk of developing urinary incontinence. Risk factors include autonomic neuropathy (causing either neurogenic bladder or fecal impaction), polyuria due to hyperglycemia, and urinary tract and vaginal infections. Although evidence is lacking that urinary incontinence affects glycemic control, assessing and treating the condition improves quality of life.

SUMMARY

Diabetes is a common problem in the elderly, accounting for considerable morbidity and mortality. In a large longitudinal analysis (> 50,000 patients), elderly persons newly diagnosed as having diabetes experienced high rates of complications during 10-year follow-up, far in excess of elderly persons without diabetes.42 Diabetes is underdiagnosed in the elderly and is frequently undertreated. Management of the elderly with diabetes presents unique challenges because of associated comorbidities, but with attention to detail and individualized approaches, quality and duration of life can be optimized. The greatest attention should be given to reduction of overall cardiovascular risk. Glycemic goals and the treatment regimens to achieve those goals should be individualized and chosen to control hyperglycemic symptoms and achieve the maximal glycemic control possible while minimizing the risk of hypoglycemia. Diabetes will continue to be a challenge to the patient, the physician, the care team, and the health care system.

References
  1. Gregg EW, Engelgau MM, Narayan V. Complications of diabetes in elderly people. BMJ 2002; 325:916917.
  2. Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001; 56:4248.
  3. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999; 53:19371942.
  4. Fontbonne A, Berr C, Ducimetiere P, Alperovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 2001; 24:366370.
  5. Gregg EW, Mangione CM, Cauley JA, et al. Diabetes and incidence of functional disability in older women. Diabetes Care 2002; 25:6167.
  6. Hornick T, Aron DC. Managing diabetes in the elderly: go easy, individualize. Cleve Clin J Med 2008; 75:7078.
  7. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229234.
  8. Bertoni AG, Krop JS, Anderson GF, Brancati FL. Diabetes-related morbidity and mortality in a national sample of U.S. elders. Diabetes Care 2002; 25:471475.
  9. Bertoni AG, Kirk JK, Goff DC, Wagenknecht LE. Excess mortality related to diabetes mellitus in elderly Medicare beneficiaries. Ann Epidemiol 2004; 14:362367.
  10. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703713. Erratum in: BMJ 1999; 318:29.
  11. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. The CARE Investigators. Circulation 1998; 98:25132519.
  12. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes. Lancet 2003; 361:20052016.
  13. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005; 28:S4S36.
  14. Brown AF, Mangione CM, Saliba D, Sarkisian CA California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes. Guidelines for improving the care of the older person with diabetes mellitus. J Am Geriatr Soc 2003; 51:S265S280.
  15. VA/DoD Clinical Practice Guideline for the Management of Diabetes Mellitus in the Primary Care Setting 2003. Accessed January 4, 2008. www.oqp.med.va.gov/cpg/dm/DM3_cpg/content/introduction.htm.
  16. Pogach LM, Brietzke SA, Cowan CL, Conlin P, Walder DJ, Sawin CT VA/DoD Diabetes Guideline Development Group. Development of evidence-based clinical practice guidelines for diabetes: the Department of Veterans Affairs/Department of Defense guidelines initiative. Diabetes Care 2004; 27:B82B89.
  17. Stratton IM, Asler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405412.
  18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837853. Erratum in: Lancet 1999; 354:602.
  19. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004; 141:413420.
  20. Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM UK Prospective Diabetes Study Group. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol 2004; 122:16311640.
  21. Cahill M, Halley A, Codd M, et al. Prevalence of diabetic retinopathy in patients with diabetic mellitus diagnosed after the age of 70 years. Br J Opthalmol 1997; 81:218222.
  22. Hirvela H, Laatikainen L. Diabetic retinopathy in people aged 70 years or older. The Oulu Eye Study. Br J Ophthalmol 1997; 81:214217.
  23. Tovi J, Ingemansson SO, Engfeldt P. Insulin treatment of elderly type 2 diabetic patients: effects on retinopathy. Diabetes Metab 1998; 24:442447.
  24. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002; 61:10861097.
  25. Kohner EM. Aspirin for diabetic retinopathy. BMJ 2003; 327:10601061.
  26. Greene DA, Stevens MJ, Feldman EL. Diabetic neuropathy: scope of the syndrome. Am J Med 1999; 107:2S8S.
  27. Hutchinson A, McIntosh A, Peters J, et al. Effectiveness of screening and monitoring tests for diabetic retinopathy—a systematic review. Diabet Med 2000; 17:495506.
  28. Vijan S, Hofer TP, Hayward RA. Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus. JAMA 2000; 283:889896.
  29. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA 2007; 298:902916.
  30. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc 2006; 81:S3S11.
  31. Wong MC, Chung JW, Wong TK. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review. BMJ 2007; 335:87: epubl June 11, 2007.
  32. Bild DE, Selby JV, Sinnock P, Browner WS, Braveman P, Showstack JA. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care 1989; 12:2431.
  33. Wheeler SG, Ahroni JH, Boyko EJ. Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes. Diabetes Res Clin Pract 2002; 58:131138.
  34. Brenner BM, Cooper ME, de Zeeuw D RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861869.
  35. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317:713720.
  36. Sinclair AJ, Girling AJ, Bayer AJ. Cognitive dysfunction in older subjects with diabetes mellitus: impact on diabetes self-management and use of care services. All Wales Research into Elderly (AWARE) Study. Diabetes Res Clin Pract 2000; 50:203212.
  37. Moisan J, Gaudet M, Gregoire JP, Bouchard R. Non-compliance with drug treatment and reading difficulties with regard to prescription labelling among seniors. Gerontology 2002; 48:4451.
  38. Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005; 294:716724.
  39. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002; 288:462467.
  40. Schwartz AV, Hillier TA, Sellmeyer DE, et al. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care 2002; 25:17491754.
  41. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention. Guideline for the prevention of falls in older persons. J Am Geriatr Soc 2001; 49:664672.
  42. Bethel MA, Sloan FA, Belsky D, Feinglos MN. Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients. Arch Intern Med 2007; 167:921927.
Article PDF
Author and Disclosure Information

Thomas Hornick, MD
Associate Professor of Medicine, Division of Geriatrics, Department of Medicine, Case Western Reserve University School of Medicine; and Director, Geriatrics Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland

David C. Aron, MD, MS
Professor of Medicine and Epidemiology and Biostatistics, Divisions of Clinical and Molecular Endocrinology and Epidemiology and Biostatistics, Department of Medicine, Case Western Reserve University School of Medicine; Associate Chief of Staff/Education and Associate Director (Health Services Research), Geriatrics Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland; member of the Performance Measures Subcommittee of the Endocrine Society, and Chair, Diabetes/Endocrine Field Advisory Committee, Department of Veterans Affairs

Address: David C. Aron, MD, MS, Education Office 14(W), Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106; e-mail [email protected]

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Publications
Topics
Page Number
153-158
Sections
Author and Disclosure Information

Thomas Hornick, MD
Associate Professor of Medicine, Division of Geriatrics, Department of Medicine, Case Western Reserve University School of Medicine; and Director, Geriatrics Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland

David C. Aron, MD, MS
Professor of Medicine and Epidemiology and Biostatistics, Divisions of Clinical and Molecular Endocrinology and Epidemiology and Biostatistics, Department of Medicine, Case Western Reserve University School of Medicine; Associate Chief of Staff/Education and Associate Director (Health Services Research), Geriatrics Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland; member of the Performance Measures Subcommittee of the Endocrine Society, and Chair, Diabetes/Endocrine Field Advisory Committee, Department of Veterans Affairs

Address: David C. Aron, MD, MS, Education Office 14(W), Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106; e-mail [email protected]

Author and Disclosure Information

Thomas Hornick, MD
Associate Professor of Medicine, Division of Geriatrics, Department of Medicine, Case Western Reserve University School of Medicine; and Director, Geriatrics Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland

David C. Aron, MD, MS
Professor of Medicine and Epidemiology and Biostatistics, Divisions of Clinical and Molecular Endocrinology and Epidemiology and Biostatistics, Department of Medicine, Case Western Reserve University School of Medicine; Associate Chief of Staff/Education and Associate Director (Health Services Research), Geriatrics Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland; member of the Performance Measures Subcommittee of the Endocrine Society, and Chair, Diabetes/Endocrine Field Advisory Committee, Department of Veterans Affairs

Address: David C. Aron, MD, MS, Education Office 14(W), Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106; e-mail [email protected]

Article PDF
Article PDF

In elderly patients, as in all patients, diabetes is much more than the blood glucose level. However, in elderly patients the disease accelerates other common conditions of that population and markedly complicates their management.

Hypertension, coronary artery disease, and cerebrovascular attacks are more common in patients with diabetes.1 Longitudinal studies of elderly and middle-aged people with diabetes show increased rates of cognitive decline and dementia.2–4 Depression, urinary incontinence, and falls are also more common in elderly patients with diabetes. Physical disability is also increased: women with diabetes are half as likely to be able to manage ordinary physical tasks such as walking, climbing stairs, and doing housework as women without diabetes.5

In an earlier paper in this journal,6 we reviewed the management of diabetes per se in elderly patients. In the pages that follow, we review the management of its associated conditions.

HEART RISK TRUMPS BLOOD SUGAR

Coronary artery disease is by far the leading cause of death in elderly people with diabetes: 40% to 50% of patients with type 2 diabetes die of cardiac disease.7–9 The conventional risk factors—hypertension, hyperlipidemia, smoking, and diabetes—remain risk factors throughout old age. Risk reduction should focus on treating hypertension and dyslipidemia, smoking cessation, aspirin therapy, and exercise. While glycemic control reduces the risk of microvascular complications (eg, diabetic retinopathy and nephropathy) after about 8 years of treatment, benefits from control of elevated blood pressure and cholesterol occur after only 2 to 3 years.

Tight control of hypertension confers significant benefit

The United Kingdom Prospective Diabetes Study (UKPDS)10 found that patients who had tight control of blood pressure (mean treated blood pressure 144/82 mm Hg) had 24% fewer diabetes-related end points, 32% fewer diabetes-related deaths, 44% fewer strokes, a 34% reduced risk of deterioration of retinopathy, and a 47% reduced risk of visual deterioration than patients who had usual control (mean treated blood pressure 157/87 mm Hg). The benefit of treating hypertension outweighed the benefits of tight glycemic control.

A strong focus on blood pressure control should be a major focus of any treatment program. The American Geriatrics Society goal for blood pressure is less than 140/80 mm Hg if tolerated. Others have proposed more stringent targets.

Lipid control

Lipid control is integral to managing elderly patients with diabetes. In the Cholesterol and Recurrent Events trial11 and the Heart Protection Study,12 the cardiovascular benefits of reducing serum low-density lipoprotein cholesterol (LDL-C) levels were similar in elderly and younger patients with diabetes. In a meta-analysis of secondary prevention trials, absolute risk reduction was greatest in subjects older than 65 years with either diabetes or diastolic hypertension.

The American Diabetes Association,13 the American Geriatrics Society,14 and the Department of Veterans Affairs15,16 have all set a goal for serum LDL-C of less than 100 mg/dL. In addition, the American Diabetes Association has set goal levels for triglycerides (< 150 mg/dL) and high-density lipoprotein cholesterol (> 40 mg/dL).

Glycemic control

The importance of tight glycemic control in preventing coronary heart disease in the elderly is somewhat controversial. Treatment guidelines for elderly patients with diabetes are mainly extrapolated from the UKPDS, in which patients were a mean of 54 years old at the start of the study. After 10 years, the mean hemoglobin A1c levels were 7.9% in patients receiving conventional control and 7.0% in patients with intensive therapy. Every 1% reduction in hemoglobin A1c was associated with a 37% decline in microvascular complications of diabetes, a 14% decline in myocardial infarctions, and a 21% decline in any diabetes-related outcome.17

In the original trial,18 the rate of myocardial infarction was 17.4% in the conventional treatment group vs 14.7% in the intensive group (P = .052), and the risk of stroke did not differ. No thresholds for realizing benefits from reducing fasting glucose or hemoglobin A1c levels were detected.

A recent cohort study involving about 10,000 participants aged 45 to 79 years found that the risk of cardiovascular disease and death from any cause increased continuously with increasing hemoglobin A1c levels in people with or without diabetes.19 However, the impact of treatment remains to be clarified. The Action to Control Cardiovascular Risk in Diabetes trial will address this question (and others), but results will not be available for several years.

 

 

RETINOPATHY IS A MAJOR CAUSE OF BLINDNESS

Diabetic retinopathy, a leading cause of blindness in the United States, is perhaps the most threatening of the chronic microvascular complications of diabetes for elderly patients. The strongest predictor of retinopathy is the duration of diabetes.20–22 Retinopathy is classified as being nonproliferative, preproliferative, or proliferative.

Ischemia is believed to be the major cause of diabetic retinopathy, and glucose control has been shown to be of major benefit. A study of young adults with type 1 diabetes found that intensive therapy reduced the risk of developing retinopathy by 76% and slowed the progression of retinopathy by 54%. Comparable data for patients with type 2 diabetes are lacking.

Of some concern is a study in which retinopathy progressed more rapidly during the first year of aggressive insulin therapy in elderly patients with diabetes and baseline retinopathy.23 Further research is needed to identify which subgroups would benefit most from aggressive glycemic control.

In addition to specific ophthalmologic treatment, managing cardiovascular risk factors may reduce the progression of retinopathy: each cardiovascular risk factor has been found to also be a risk factor for retinopathy. Hypertension is an independent risk factor for any retinopathy, and its tight control reduces progression.20,24 Aspirin therapy has not been found to confer either risk or benefit.25,26

Although guidelines typically call for yearly ophthalmic examinations to screen for retinopathy, whether this is cost-effective has been questioned.27,28 But people older than 65 years with diabetes also have twice the risk of developing cataracts and three times the risk of developing glaucoma than those without diabetes. Considering the effects of visual loss on quality of life as well as the subsequent higher risk of accidents, eye examinations by an ophthalmologist at the time of diagnosis and annually thereafter are recommended. Tight glycemic and blood pressure control remains the cornerstone in the primary prevention of diabetic retinopathy. Panretinal and focal retinal laser photocoagulation reduces the risk of visual loss in patients with severe retinopathy and macular edema, respectively.29

NEUROPATHY PRESENTS IN MANY FORMS

Neuropathy is a particularly distressing complication and can lead to loss of sleep, limitation of activity, and depression.26,30,31 Diabetic neuropathies include focal neuropathies (entrapment syndromes and mono-neuropathies), polyneuropathy, and autonomic neuropathy.

Distal symmetric polyneuropathy (“glove and stocking” sensory symptoms) is the most common neuropathy of elderly people with diabetes. Pain, which can interrupt sleep and limit activity, can be treated with the anticonvulsants gabapentin (Gabarone, Neurontin), phenytoin (Dilantin, Phenytek) and carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), and with tricyclic antidepressants. However, the anticholinergic effects of tricyclic antidepressants limit their use in older patients. Newer agents, such as duloxetine (Cymbalta) and pregabalin (Lyrica) show promise.30,31 Dysesthesia of a burning quality is sometimes treated with topical capsaicin or with oral mexiletine (Mexitil), although their role in treating older patients is not well established.

Patients with distal sensory polyneuropathy are predisposed to develop Charcot joints, which may mimic gout or degenerative joint disease. Plain radiography of the foot can help differentiate these diseases. Distal sensory polyneuropathy also predisposes patients to neuropathic foot ulcer, the leading cause of foot amputation in the United States.32

Feet should be inspected at each office visit. Testing sensation with a monofilament detects sensory neuropathy. Patients should be encouraged to examine their feet daily. Therapeutic shoes, prescribed by a podiatrist and individually designed to prevent blisters, calluses, and ulcers, are covered by Medicare for peripheral neuropathy if any of the following are also present: callus formation, poor circulation, foot deformity, or a history of foot callus, ulcer, or amputation (partial or complete). Medicare will pay for one pair of shoes plus three pairs of inserts per year.

Proximal motor neuropathy (diabetic amyotrophy) primarily affects elderly patients. It begins with unilateral thigh pain, which becomes bilateral and progresses to proximal muscle weakness and wasting. Distal symmetric polyneuropathy may also be present. Treatment includes glycemic control (usually with insulin) and physical therapy. Some forms of amyotrophy respond to immunotherapy.

Autonomic neuropathy, although not painful, can be the most life-threatening form of diabetic neuropathy.33 Tachycardia increases the risk of sudden death, while postural hypotension increases the risk of syncope, falling, and injury. Other forms of autonomic neuropathy include neurogenic bladder, sexual dysfunction, gastropathy (which is particularly sensitive to glycemic control), enteropathy, and gustatory sweating. Patients with autonomic neuropathy are more likely to have hypoglycemic unawareness.

 

 

NEPHROPATHY CAN PROGRESS RAPIDLY

Elderly patients with diabetes are especially at risk of developing nephropathy, which progresses from microalbuminuria to overt proteinuria to renal insufficiency and end-stage renal disease. Nephropathy may develop over a shorter time than the typical 10 to 20 years in younger patients. Independent risk factors for proteinuria and renal insufficiency include poor glycemic control over many years, hypertension, longer duration of diabetes, male sex, high serum total cholesterol levels, and smoking. Elderly patients are also at risk of renal insults such as receiving intravenous iodinated contrast agents in the course of radiologic procedures, nephrotoxic drugs, and comorbid illness such as congestive heart failure.

The diagnosis of diabetic nephropathy is usually made clinically and not by renal biopsy. Diabetic nephropathy can be diagnosed with almost 100% specificity in type 1 diabetes and more than 85% specificity in type 2 diabetes by a urinary albumin excretion of more than 300 mg per day and an appropriate time course in the absence of other obvious causes of renal disease. The urinary albumin-to-creatinine ratio can be used to screen for microalbuminuria (the precursor of frank proteinuria and renal insufficiency). A value of more than 30 mg of albumin per gram of creatinine suggests that albumin excretion exceeds 30 mg and that microalbuminuria is present.

Prevention is a cornerstone of management. Good glycemic control reduces the risk of microalbuminuria, the progression of albuminuria, and the development of renal insufficiency. Lowering blood pressure reduces the decline in glomerular filtration rate and albuminuria. Angiotensin-converting enzyme (ACE) inhibitors reduce the rate of progression of proteinuria and reduce the rate of end-stage renal disease, although the data are stronger in patients with type 1 diabetes.34 When side effects such as cough limit the use of ACE inhibitors, angiotensin receptor blockers can be used as an alternative. Blood pressure should be controlled to reduce stroke and cardiovascular complications, regardless of whether microalbuminuria is present.35

End-stage renal disease in elderly patients with diabetes is becoming increasingly frequent. Nephropathy in older patients is different from that in younger patients. In elderly patients, the pathologic findings may suggest ischemia and hypertension, and the classic Kimmelstiel-Wilson lesions may be absent. Patients may present with end-stage renal disease following an episode of acute renal failure that does not resolve, which may occur after a radiologic procedure involving an iodinated contrast agent.

NONKETOTIC HYPEROSMOLAR COMA

Nonketotic hyperosmolar coma occurs predominantly in elderly patients with type 2 diabetes. Predisposing factors include dementia, infection, stroke, and myocardial infarction. Coma results from osmotic diuresis due to hyperglycemia and consequent dehydration. A drop in the glomerular filtration rate promotes further hyperglycemia and dehydration in a vicious circle. Glucose levels commonly reach 600 mg/dL or more, and serum osmolality often exceeds 320 mOsm/L. A fluid deficit of 5 to 10 L is typical.

Fluid replacement is the mainstay of treatment. Because free water is typically lost in an osmotic diuresis, 0.9% (normal) saline is usually given if hemodynamic instability is present or 0.45% (half-normal) saline otherwise. Insulin is also required, as is specific treatment of the precipitating cause, eg, infection. Ketoacidosis may also occur in the elderly.

Recovery from coma or improvement in mental status may lag behind correction of the serum osmolality and may take several days. Mortality rates can be high: severe hyperosmolarity, advanced age, and nursing home residence are the major risk factors for death.

INFECTIONS: SEVERE AND UNUSUAL

Elderly patients with diabetes are at increased risk of developing severe and unusual infections, particularly malignant external otitis. Necrotizing Pseudomonas aeruginosa infection initially involves the external ear canal and progresses to the mastoid air cells, the skull base, or temporal bone. The clinical presentation consists of fever, otalgia, otorrhea, and less commonly, cranial nerve palsy. Treatment involves surgical debridement and antibiotics.

Other infections associated with diabetes include rhinocerebral mucormycosis, necrotizing fasciitis, emphysematous cholecystitis, and emphysematous pyelonephritis. An elderly patient with diabetes is also at increased risk of renal papillary necrosis, which presents as insidious renal failure.

COGNITIVE IMPAIRMENT

Elderly people with diabetes are at increased risk of cognitive impairment, which poses a barrier to taking medications appropriately and performing other tasks of self-management.

Because dementia may go undetected, particularly in the early stages, cognitive function should be assessed in elderly patients when they fail to take therapy correctly or have frequent episodes of hypoglycemia, or if glycemic control deteriorates without an obvious explanation. Caregivers play a critical role in detecting and reporting early cognitive impairment.

DEPRESSION IS OFTEN UNDETECTED

Elderly patients with diabetes have a higher rate of depression than do age-matched controls, but it is commonly underdetected and undertreated.5,36 Depression has been associated with poor glycemic control, and treatment of depression is associated with improved control. Routine screening for depression should be performed; a variety of diagnostic instruments are available. Particular attention should be given to medications that are associated with depression.

 

 

POLYPHARMACY

Many elderly patients take multiple medications. Polypharmacy increases the risk of drug side effects, interactions, and nonadherence to taking medications.37–39 This problem is increased in diabetes, in which several medications are necessary to manage hyper-glycemia, hyperlipidemia, hypertension, and other associated conditions.

Patients should keep accurate medication lists, including over-the-counter medications, herbs, and nutritional supplements. Physicians should carefully review each medication to check if it is appropriate and used correctly.

FALLS

Elderly patients with diabetes mellitus are at increased risk of injurious falls, which are associated with high rates of complications, death, and functional decline.40,41 Risk factors include frailty and functional disability, visual impairment, peripheral or autonomic neuropathy, hypoglycemia, and polypharmacy.

Elderly patients should be screened for their risk of falls, and appropriate measures should be instituted. The American Geriatrics Society has guidelines for preventing falls in the elderly.41

URINARY INCONTINENCE

Elderly women with diabetes are at increased risk of developing urinary incontinence. Risk factors include autonomic neuropathy (causing either neurogenic bladder or fecal impaction), polyuria due to hyperglycemia, and urinary tract and vaginal infections. Although evidence is lacking that urinary incontinence affects glycemic control, assessing and treating the condition improves quality of life.

SUMMARY

Diabetes is a common problem in the elderly, accounting for considerable morbidity and mortality. In a large longitudinal analysis (> 50,000 patients), elderly persons newly diagnosed as having diabetes experienced high rates of complications during 10-year follow-up, far in excess of elderly persons without diabetes.42 Diabetes is underdiagnosed in the elderly and is frequently undertreated. Management of the elderly with diabetes presents unique challenges because of associated comorbidities, but with attention to detail and individualized approaches, quality and duration of life can be optimized. The greatest attention should be given to reduction of overall cardiovascular risk. Glycemic goals and the treatment regimens to achieve those goals should be individualized and chosen to control hyperglycemic symptoms and achieve the maximal glycemic control possible while minimizing the risk of hypoglycemia. Diabetes will continue to be a challenge to the patient, the physician, the care team, and the health care system.

In elderly patients, as in all patients, diabetes is much more than the blood glucose level. However, in elderly patients the disease accelerates other common conditions of that population and markedly complicates their management.

Hypertension, coronary artery disease, and cerebrovascular attacks are more common in patients with diabetes.1 Longitudinal studies of elderly and middle-aged people with diabetes show increased rates of cognitive decline and dementia.2–4 Depression, urinary incontinence, and falls are also more common in elderly patients with diabetes. Physical disability is also increased: women with diabetes are half as likely to be able to manage ordinary physical tasks such as walking, climbing stairs, and doing housework as women without diabetes.5

In an earlier paper in this journal,6 we reviewed the management of diabetes per se in elderly patients. In the pages that follow, we review the management of its associated conditions.

HEART RISK TRUMPS BLOOD SUGAR

Coronary artery disease is by far the leading cause of death in elderly people with diabetes: 40% to 50% of patients with type 2 diabetes die of cardiac disease.7–9 The conventional risk factors—hypertension, hyperlipidemia, smoking, and diabetes—remain risk factors throughout old age. Risk reduction should focus on treating hypertension and dyslipidemia, smoking cessation, aspirin therapy, and exercise. While glycemic control reduces the risk of microvascular complications (eg, diabetic retinopathy and nephropathy) after about 8 years of treatment, benefits from control of elevated blood pressure and cholesterol occur after only 2 to 3 years.

Tight control of hypertension confers significant benefit

The United Kingdom Prospective Diabetes Study (UKPDS)10 found that patients who had tight control of blood pressure (mean treated blood pressure 144/82 mm Hg) had 24% fewer diabetes-related end points, 32% fewer diabetes-related deaths, 44% fewer strokes, a 34% reduced risk of deterioration of retinopathy, and a 47% reduced risk of visual deterioration than patients who had usual control (mean treated blood pressure 157/87 mm Hg). The benefit of treating hypertension outweighed the benefits of tight glycemic control.

A strong focus on blood pressure control should be a major focus of any treatment program. The American Geriatrics Society goal for blood pressure is less than 140/80 mm Hg if tolerated. Others have proposed more stringent targets.

Lipid control

Lipid control is integral to managing elderly patients with diabetes. In the Cholesterol and Recurrent Events trial11 and the Heart Protection Study,12 the cardiovascular benefits of reducing serum low-density lipoprotein cholesterol (LDL-C) levels were similar in elderly and younger patients with diabetes. In a meta-analysis of secondary prevention trials, absolute risk reduction was greatest in subjects older than 65 years with either diabetes or diastolic hypertension.

The American Diabetes Association,13 the American Geriatrics Society,14 and the Department of Veterans Affairs15,16 have all set a goal for serum LDL-C of less than 100 mg/dL. In addition, the American Diabetes Association has set goal levels for triglycerides (< 150 mg/dL) and high-density lipoprotein cholesterol (> 40 mg/dL).

Glycemic control

The importance of tight glycemic control in preventing coronary heart disease in the elderly is somewhat controversial. Treatment guidelines for elderly patients with diabetes are mainly extrapolated from the UKPDS, in which patients were a mean of 54 years old at the start of the study. After 10 years, the mean hemoglobin A1c levels were 7.9% in patients receiving conventional control and 7.0% in patients with intensive therapy. Every 1% reduction in hemoglobin A1c was associated with a 37% decline in microvascular complications of diabetes, a 14% decline in myocardial infarctions, and a 21% decline in any diabetes-related outcome.17

In the original trial,18 the rate of myocardial infarction was 17.4% in the conventional treatment group vs 14.7% in the intensive group (P = .052), and the risk of stroke did not differ. No thresholds for realizing benefits from reducing fasting glucose or hemoglobin A1c levels were detected.

A recent cohort study involving about 10,000 participants aged 45 to 79 years found that the risk of cardiovascular disease and death from any cause increased continuously with increasing hemoglobin A1c levels in people with or without diabetes.19 However, the impact of treatment remains to be clarified. The Action to Control Cardiovascular Risk in Diabetes trial will address this question (and others), but results will not be available for several years.

 

 

RETINOPATHY IS A MAJOR CAUSE OF BLINDNESS

Diabetic retinopathy, a leading cause of blindness in the United States, is perhaps the most threatening of the chronic microvascular complications of diabetes for elderly patients. The strongest predictor of retinopathy is the duration of diabetes.20–22 Retinopathy is classified as being nonproliferative, preproliferative, or proliferative.

Ischemia is believed to be the major cause of diabetic retinopathy, and glucose control has been shown to be of major benefit. A study of young adults with type 1 diabetes found that intensive therapy reduced the risk of developing retinopathy by 76% and slowed the progression of retinopathy by 54%. Comparable data for patients with type 2 diabetes are lacking.

Of some concern is a study in which retinopathy progressed more rapidly during the first year of aggressive insulin therapy in elderly patients with diabetes and baseline retinopathy.23 Further research is needed to identify which subgroups would benefit most from aggressive glycemic control.

In addition to specific ophthalmologic treatment, managing cardiovascular risk factors may reduce the progression of retinopathy: each cardiovascular risk factor has been found to also be a risk factor for retinopathy. Hypertension is an independent risk factor for any retinopathy, and its tight control reduces progression.20,24 Aspirin therapy has not been found to confer either risk or benefit.25,26

Although guidelines typically call for yearly ophthalmic examinations to screen for retinopathy, whether this is cost-effective has been questioned.27,28 But people older than 65 years with diabetes also have twice the risk of developing cataracts and three times the risk of developing glaucoma than those without diabetes. Considering the effects of visual loss on quality of life as well as the subsequent higher risk of accidents, eye examinations by an ophthalmologist at the time of diagnosis and annually thereafter are recommended. Tight glycemic and blood pressure control remains the cornerstone in the primary prevention of diabetic retinopathy. Panretinal and focal retinal laser photocoagulation reduces the risk of visual loss in patients with severe retinopathy and macular edema, respectively.29

NEUROPATHY PRESENTS IN MANY FORMS

Neuropathy is a particularly distressing complication and can lead to loss of sleep, limitation of activity, and depression.26,30,31 Diabetic neuropathies include focal neuropathies (entrapment syndromes and mono-neuropathies), polyneuropathy, and autonomic neuropathy.

Distal symmetric polyneuropathy (“glove and stocking” sensory symptoms) is the most common neuropathy of elderly people with diabetes. Pain, which can interrupt sleep and limit activity, can be treated with the anticonvulsants gabapentin (Gabarone, Neurontin), phenytoin (Dilantin, Phenytek) and carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), and with tricyclic antidepressants. However, the anticholinergic effects of tricyclic antidepressants limit their use in older patients. Newer agents, such as duloxetine (Cymbalta) and pregabalin (Lyrica) show promise.30,31 Dysesthesia of a burning quality is sometimes treated with topical capsaicin or with oral mexiletine (Mexitil), although their role in treating older patients is not well established.

Patients with distal sensory polyneuropathy are predisposed to develop Charcot joints, which may mimic gout or degenerative joint disease. Plain radiography of the foot can help differentiate these diseases. Distal sensory polyneuropathy also predisposes patients to neuropathic foot ulcer, the leading cause of foot amputation in the United States.32

Feet should be inspected at each office visit. Testing sensation with a monofilament detects sensory neuropathy. Patients should be encouraged to examine their feet daily. Therapeutic shoes, prescribed by a podiatrist and individually designed to prevent blisters, calluses, and ulcers, are covered by Medicare for peripheral neuropathy if any of the following are also present: callus formation, poor circulation, foot deformity, or a history of foot callus, ulcer, or amputation (partial or complete). Medicare will pay for one pair of shoes plus three pairs of inserts per year.

Proximal motor neuropathy (diabetic amyotrophy) primarily affects elderly patients. It begins with unilateral thigh pain, which becomes bilateral and progresses to proximal muscle weakness and wasting. Distal symmetric polyneuropathy may also be present. Treatment includes glycemic control (usually with insulin) and physical therapy. Some forms of amyotrophy respond to immunotherapy.

Autonomic neuropathy, although not painful, can be the most life-threatening form of diabetic neuropathy.33 Tachycardia increases the risk of sudden death, while postural hypotension increases the risk of syncope, falling, and injury. Other forms of autonomic neuropathy include neurogenic bladder, sexual dysfunction, gastropathy (which is particularly sensitive to glycemic control), enteropathy, and gustatory sweating. Patients with autonomic neuropathy are more likely to have hypoglycemic unawareness.

 

 

NEPHROPATHY CAN PROGRESS RAPIDLY

Elderly patients with diabetes are especially at risk of developing nephropathy, which progresses from microalbuminuria to overt proteinuria to renal insufficiency and end-stage renal disease. Nephropathy may develop over a shorter time than the typical 10 to 20 years in younger patients. Independent risk factors for proteinuria and renal insufficiency include poor glycemic control over many years, hypertension, longer duration of diabetes, male sex, high serum total cholesterol levels, and smoking. Elderly patients are also at risk of renal insults such as receiving intravenous iodinated contrast agents in the course of radiologic procedures, nephrotoxic drugs, and comorbid illness such as congestive heart failure.

The diagnosis of diabetic nephropathy is usually made clinically and not by renal biopsy. Diabetic nephropathy can be diagnosed with almost 100% specificity in type 1 diabetes and more than 85% specificity in type 2 diabetes by a urinary albumin excretion of more than 300 mg per day and an appropriate time course in the absence of other obvious causes of renal disease. The urinary albumin-to-creatinine ratio can be used to screen for microalbuminuria (the precursor of frank proteinuria and renal insufficiency). A value of more than 30 mg of albumin per gram of creatinine suggests that albumin excretion exceeds 30 mg and that microalbuminuria is present.

Prevention is a cornerstone of management. Good glycemic control reduces the risk of microalbuminuria, the progression of albuminuria, and the development of renal insufficiency. Lowering blood pressure reduces the decline in glomerular filtration rate and albuminuria. Angiotensin-converting enzyme (ACE) inhibitors reduce the rate of progression of proteinuria and reduce the rate of end-stage renal disease, although the data are stronger in patients with type 1 diabetes.34 When side effects such as cough limit the use of ACE inhibitors, angiotensin receptor blockers can be used as an alternative. Blood pressure should be controlled to reduce stroke and cardiovascular complications, regardless of whether microalbuminuria is present.35

End-stage renal disease in elderly patients with diabetes is becoming increasingly frequent. Nephropathy in older patients is different from that in younger patients. In elderly patients, the pathologic findings may suggest ischemia and hypertension, and the classic Kimmelstiel-Wilson lesions may be absent. Patients may present with end-stage renal disease following an episode of acute renal failure that does not resolve, which may occur after a radiologic procedure involving an iodinated contrast agent.

NONKETOTIC HYPEROSMOLAR COMA

Nonketotic hyperosmolar coma occurs predominantly in elderly patients with type 2 diabetes. Predisposing factors include dementia, infection, stroke, and myocardial infarction. Coma results from osmotic diuresis due to hyperglycemia and consequent dehydration. A drop in the glomerular filtration rate promotes further hyperglycemia and dehydration in a vicious circle. Glucose levels commonly reach 600 mg/dL or more, and serum osmolality often exceeds 320 mOsm/L. A fluid deficit of 5 to 10 L is typical.

Fluid replacement is the mainstay of treatment. Because free water is typically lost in an osmotic diuresis, 0.9% (normal) saline is usually given if hemodynamic instability is present or 0.45% (half-normal) saline otherwise. Insulin is also required, as is specific treatment of the precipitating cause, eg, infection. Ketoacidosis may also occur in the elderly.

Recovery from coma or improvement in mental status may lag behind correction of the serum osmolality and may take several days. Mortality rates can be high: severe hyperosmolarity, advanced age, and nursing home residence are the major risk factors for death.

INFECTIONS: SEVERE AND UNUSUAL

Elderly patients with diabetes are at increased risk of developing severe and unusual infections, particularly malignant external otitis. Necrotizing Pseudomonas aeruginosa infection initially involves the external ear canal and progresses to the mastoid air cells, the skull base, or temporal bone. The clinical presentation consists of fever, otalgia, otorrhea, and less commonly, cranial nerve palsy. Treatment involves surgical debridement and antibiotics.

Other infections associated with diabetes include rhinocerebral mucormycosis, necrotizing fasciitis, emphysematous cholecystitis, and emphysematous pyelonephritis. An elderly patient with diabetes is also at increased risk of renal papillary necrosis, which presents as insidious renal failure.

COGNITIVE IMPAIRMENT

Elderly people with diabetes are at increased risk of cognitive impairment, which poses a barrier to taking medications appropriately and performing other tasks of self-management.

Because dementia may go undetected, particularly in the early stages, cognitive function should be assessed in elderly patients when they fail to take therapy correctly or have frequent episodes of hypoglycemia, or if glycemic control deteriorates without an obvious explanation. Caregivers play a critical role in detecting and reporting early cognitive impairment.

DEPRESSION IS OFTEN UNDETECTED

Elderly patients with diabetes have a higher rate of depression than do age-matched controls, but it is commonly underdetected and undertreated.5,36 Depression has been associated with poor glycemic control, and treatment of depression is associated with improved control. Routine screening for depression should be performed; a variety of diagnostic instruments are available. Particular attention should be given to medications that are associated with depression.

 

 

POLYPHARMACY

Many elderly patients take multiple medications. Polypharmacy increases the risk of drug side effects, interactions, and nonadherence to taking medications.37–39 This problem is increased in diabetes, in which several medications are necessary to manage hyper-glycemia, hyperlipidemia, hypertension, and other associated conditions.

Patients should keep accurate medication lists, including over-the-counter medications, herbs, and nutritional supplements. Physicians should carefully review each medication to check if it is appropriate and used correctly.

FALLS

Elderly patients with diabetes mellitus are at increased risk of injurious falls, which are associated with high rates of complications, death, and functional decline.40,41 Risk factors include frailty and functional disability, visual impairment, peripheral or autonomic neuropathy, hypoglycemia, and polypharmacy.

Elderly patients should be screened for their risk of falls, and appropriate measures should be instituted. The American Geriatrics Society has guidelines for preventing falls in the elderly.41

URINARY INCONTINENCE

Elderly women with diabetes are at increased risk of developing urinary incontinence. Risk factors include autonomic neuropathy (causing either neurogenic bladder or fecal impaction), polyuria due to hyperglycemia, and urinary tract and vaginal infections. Although evidence is lacking that urinary incontinence affects glycemic control, assessing and treating the condition improves quality of life.

SUMMARY

Diabetes is a common problem in the elderly, accounting for considerable morbidity and mortality. In a large longitudinal analysis (> 50,000 patients), elderly persons newly diagnosed as having diabetes experienced high rates of complications during 10-year follow-up, far in excess of elderly persons without diabetes.42 Diabetes is underdiagnosed in the elderly and is frequently undertreated. Management of the elderly with diabetes presents unique challenges because of associated comorbidities, but with attention to detail and individualized approaches, quality and duration of life can be optimized. The greatest attention should be given to reduction of overall cardiovascular risk. Glycemic goals and the treatment regimens to achieve those goals should be individualized and chosen to control hyperglycemic symptoms and achieve the maximal glycemic control possible while minimizing the risk of hypoglycemia. Diabetes will continue to be a challenge to the patient, the physician, the care team, and the health care system.

References
  1. Gregg EW, Engelgau MM, Narayan V. Complications of diabetes in elderly people. BMJ 2002; 325:916917.
  2. Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001; 56:4248.
  3. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999; 53:19371942.
  4. Fontbonne A, Berr C, Ducimetiere P, Alperovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 2001; 24:366370.
  5. Gregg EW, Mangione CM, Cauley JA, et al. Diabetes and incidence of functional disability in older women. Diabetes Care 2002; 25:6167.
  6. Hornick T, Aron DC. Managing diabetes in the elderly: go easy, individualize. Cleve Clin J Med 2008; 75:7078.
  7. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229234.
  8. Bertoni AG, Krop JS, Anderson GF, Brancati FL. Diabetes-related morbidity and mortality in a national sample of U.S. elders. Diabetes Care 2002; 25:471475.
  9. Bertoni AG, Kirk JK, Goff DC, Wagenknecht LE. Excess mortality related to diabetes mellitus in elderly Medicare beneficiaries. Ann Epidemiol 2004; 14:362367.
  10. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703713. Erratum in: BMJ 1999; 318:29.
  11. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. The CARE Investigators. Circulation 1998; 98:25132519.
  12. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes. Lancet 2003; 361:20052016.
  13. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005; 28:S4S36.
  14. Brown AF, Mangione CM, Saliba D, Sarkisian CA California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes. Guidelines for improving the care of the older person with diabetes mellitus. J Am Geriatr Soc 2003; 51:S265S280.
  15. VA/DoD Clinical Practice Guideline for the Management of Diabetes Mellitus in the Primary Care Setting 2003. Accessed January 4, 2008. www.oqp.med.va.gov/cpg/dm/DM3_cpg/content/introduction.htm.
  16. Pogach LM, Brietzke SA, Cowan CL, Conlin P, Walder DJ, Sawin CT VA/DoD Diabetes Guideline Development Group. Development of evidence-based clinical practice guidelines for diabetes: the Department of Veterans Affairs/Department of Defense guidelines initiative. Diabetes Care 2004; 27:B82B89.
  17. Stratton IM, Asler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405412.
  18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837853. Erratum in: Lancet 1999; 354:602.
  19. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004; 141:413420.
  20. Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM UK Prospective Diabetes Study Group. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol 2004; 122:16311640.
  21. Cahill M, Halley A, Codd M, et al. Prevalence of diabetic retinopathy in patients with diabetic mellitus diagnosed after the age of 70 years. Br J Opthalmol 1997; 81:218222.
  22. Hirvela H, Laatikainen L. Diabetic retinopathy in people aged 70 years or older. The Oulu Eye Study. Br J Ophthalmol 1997; 81:214217.
  23. Tovi J, Ingemansson SO, Engfeldt P. Insulin treatment of elderly type 2 diabetic patients: effects on retinopathy. Diabetes Metab 1998; 24:442447.
  24. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002; 61:10861097.
  25. Kohner EM. Aspirin for diabetic retinopathy. BMJ 2003; 327:10601061.
  26. Greene DA, Stevens MJ, Feldman EL. Diabetic neuropathy: scope of the syndrome. Am J Med 1999; 107:2S8S.
  27. Hutchinson A, McIntosh A, Peters J, et al. Effectiveness of screening and monitoring tests for diabetic retinopathy—a systematic review. Diabet Med 2000; 17:495506.
  28. Vijan S, Hofer TP, Hayward RA. Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus. JAMA 2000; 283:889896.
  29. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA 2007; 298:902916.
  30. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc 2006; 81:S3S11.
  31. Wong MC, Chung JW, Wong TK. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review. BMJ 2007; 335:87: epubl June 11, 2007.
  32. Bild DE, Selby JV, Sinnock P, Browner WS, Braveman P, Showstack JA. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care 1989; 12:2431.
  33. Wheeler SG, Ahroni JH, Boyko EJ. Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes. Diabetes Res Clin Pract 2002; 58:131138.
  34. Brenner BM, Cooper ME, de Zeeuw D RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861869.
  35. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317:713720.
  36. Sinclair AJ, Girling AJ, Bayer AJ. Cognitive dysfunction in older subjects with diabetes mellitus: impact on diabetes self-management and use of care services. All Wales Research into Elderly (AWARE) Study. Diabetes Res Clin Pract 2000; 50:203212.
  37. Moisan J, Gaudet M, Gregoire JP, Bouchard R. Non-compliance with drug treatment and reading difficulties with regard to prescription labelling among seniors. Gerontology 2002; 48:4451.
  38. Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005; 294:716724.
  39. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002; 288:462467.
  40. Schwartz AV, Hillier TA, Sellmeyer DE, et al. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care 2002; 25:17491754.
  41. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention. Guideline for the prevention of falls in older persons. J Am Geriatr Soc 2001; 49:664672.
  42. Bethel MA, Sloan FA, Belsky D, Feinglos MN. Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients. Arch Intern Med 2007; 167:921927.
References
  1. Gregg EW, Engelgau MM, Narayan V. Complications of diabetes in elderly people. BMJ 2002; 325:916917.
  2. Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001; 56:4248.
  3. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999; 53:19371942.
  4. Fontbonne A, Berr C, Ducimetiere P, Alperovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 2001; 24:366370.
  5. Gregg EW, Mangione CM, Cauley JA, et al. Diabetes and incidence of functional disability in older women. Diabetes Care 2002; 25:6167.
  6. Hornick T, Aron DC. Managing diabetes in the elderly: go easy, individualize. Cleve Clin J Med 2008; 75:7078.
  7. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229234.
  8. Bertoni AG, Krop JS, Anderson GF, Brancati FL. Diabetes-related morbidity and mortality in a national sample of U.S. elders. Diabetes Care 2002; 25:471475.
  9. Bertoni AG, Kirk JK, Goff DC, Wagenknecht LE. Excess mortality related to diabetes mellitus in elderly Medicare beneficiaries. Ann Epidemiol 2004; 14:362367.
  10. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703713. Erratum in: BMJ 1999; 318:29.
  11. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. The CARE Investigators. Circulation 1998; 98:25132519.
  12. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes. Lancet 2003; 361:20052016.
  13. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005; 28:S4S36.
  14. Brown AF, Mangione CM, Saliba D, Sarkisian CA California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes. Guidelines for improving the care of the older person with diabetes mellitus. J Am Geriatr Soc 2003; 51:S265S280.
  15. VA/DoD Clinical Practice Guideline for the Management of Diabetes Mellitus in the Primary Care Setting 2003. Accessed January 4, 2008. www.oqp.med.va.gov/cpg/dm/DM3_cpg/content/introduction.htm.
  16. Pogach LM, Brietzke SA, Cowan CL, Conlin P, Walder DJ, Sawin CT VA/DoD Diabetes Guideline Development Group. Development of evidence-based clinical practice guidelines for diabetes: the Department of Veterans Affairs/Department of Defense guidelines initiative. Diabetes Care 2004; 27:B82B89.
  17. Stratton IM, Asler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405412.
  18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837853. Erratum in: Lancet 1999; 354:602.
  19. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004; 141:413420.
  20. Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM UK Prospective Diabetes Study Group. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol 2004; 122:16311640.
  21. Cahill M, Halley A, Codd M, et al. Prevalence of diabetic retinopathy in patients with diabetic mellitus diagnosed after the age of 70 years. Br J Opthalmol 1997; 81:218222.
  22. Hirvela H, Laatikainen L. Diabetic retinopathy in people aged 70 years or older. The Oulu Eye Study. Br J Ophthalmol 1997; 81:214217.
  23. Tovi J, Ingemansson SO, Engfeldt P. Insulin treatment of elderly type 2 diabetic patients: effects on retinopathy. Diabetes Metab 1998; 24:442447.
  24. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002; 61:10861097.
  25. Kohner EM. Aspirin for diabetic retinopathy. BMJ 2003; 327:10601061.
  26. Greene DA, Stevens MJ, Feldman EL. Diabetic neuropathy: scope of the syndrome. Am J Med 1999; 107:2S8S.
  27. Hutchinson A, McIntosh A, Peters J, et al. Effectiveness of screening and monitoring tests for diabetic retinopathy—a systematic review. Diabet Med 2000; 17:495506.
  28. Vijan S, Hofer TP, Hayward RA. Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus. JAMA 2000; 283:889896.
  29. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA 2007; 298:902916.
  30. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc 2006; 81:S3S11.
  31. Wong MC, Chung JW, Wong TK. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review. BMJ 2007; 335:87: epubl June 11, 2007.
  32. Bild DE, Selby JV, Sinnock P, Browner WS, Braveman P, Showstack JA. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care 1989; 12:2431.
  33. Wheeler SG, Ahroni JH, Boyko EJ. Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes. Diabetes Res Clin Pract 2002; 58:131138.
  34. Brenner BM, Cooper ME, de Zeeuw D RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861869.
  35. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317:713720.
  36. Sinclair AJ, Girling AJ, Bayer AJ. Cognitive dysfunction in older subjects with diabetes mellitus: impact on diabetes self-management and use of care services. All Wales Research into Elderly (AWARE) Study. Diabetes Res Clin Pract 2000; 50:203212.
  37. Moisan J, Gaudet M, Gregoire JP, Bouchard R. Non-compliance with drug treatment and reading difficulties with regard to prescription labelling among seniors. Gerontology 2002; 48:4451.
  38. Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005; 294:716724.
  39. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002; 288:462467.
  40. Schwartz AV, Hillier TA, Sellmeyer DE, et al. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care 2002; 25:17491754.
  41. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention. Guideline for the prevention of falls in older persons. J Am Geriatr Soc 2001; 49:664672.
  42. Bethel MA, Sloan FA, Belsky D, Feinglos MN. Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients. Arch Intern Med 2007; 167:921927.
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Page Number
153-158
Page Number
153-158
Publications
Publications
Topics
Article Type
Display Headline
Preventing and managing diabetic complications in elderly patients
Display Headline
Preventing and managing diabetic complications in elderly patients
Sections
Inside the Article

KEY POINTS

  • Compared with strict glycemic control, treating cardiovascular risk factors offers more benefit in a shorter time and should be a higher priority.
  • Diabetic retinopathy is a leading cause of blindness. Yearly eye examinations are recommended.
  • Elderly patients with diabetes are prone to rapidly progressive nephropathy, especially after receiving iodinated contrast agents. Good glycemic control and control of blood pressure, especially with angiotensin-converting enzyme inhibitors, reduce the risk and the rate of progression.
  • Elderly patients with diabetes are at higher risk of cognitive decline, depression, and polypharmacy, all of which impede good diabetes management.
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

A young man with acute weakness of his right arm

Article Type
Changed
Tue, 04/17/2018 - 08:34
Display Headline
A young man with acute weakness of his right arm

A 42-year-old man was working at his computer when he suddenly became disoriented and lightheaded, had difficulty concentrating, and could not move his right arm. He could walk without difficulty, but he had a tingling sensation in his right leg. He did not lose consciousness or have any associated palpitations, chest pain, shortness of breath, nausea, vomiting, headaches, or visual changes.

He called 911, and an ambulance arrived 15 minutes later. By that time his symptoms had started to resolve. Now, in the emergency department, his only residual symptom is mild numbness of his right arm and shoulder.

Until now he has been healthy except for a history of dyslipidemia. He takes no prescription or over-the-counter medications and has no drug allergies. He has smoked one pack of cigarettes daily for the past 28 years and also smokes marijuana several times each month. He drinks alcohol occasionally. His family has no history of stroke, premature coronary artery disease, or sudden cardiac death.

INITIAL EVALUATION

His heart rate is 88 beats per minute, blood pressure 142/82 mm Hg, and blood oxygen saturation 98% while breathing room air. He is alert and in no acute distress and answers questions appropriately.

His breathing sounds are normal, without crackles or wheezes. His heart has normal first and second sounds, a normal rate and rhythm, and no extra sounds or murmurs. His abdomen is normal. His extremities are warm and well perfused with normal peripheral pulses and no edema.

On neurologic examination, his cranial nerves and visual fields are normal, and his strength is normal in all muscle groups except for the right upper arm, which is slightly weaker than the left when tested against resistance. Reflexes and response to light touch and pinprick are normal.

His serum chemistry levels, renal function, and blood counts are normal. His total cholesterol level is 155 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, low-density lipoprotein cholesterol 108 mg/dL, and triglycerides 1,286 mg/dL. Electrocardiography is normal with sinus rhythm at a rate of 74.

Magnetic resonance imaging (MRI) of the head and neck with magnetic resonance angiography (MRA) of the intracranial and extracranial vessels is performed. Diffusion-weighted images show a hyperintense lesion in the left insular cortex, consistent with an infarct in the distribution of a branch of the left middle cerebral artery. There is no intracranial hemorrhage. All intracranial and extracranial major vessels are patent, and no stenoses are seen.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s stroke?

  • Vertebral or carotid atherosclerosis
  • Cervical arterial dissection
  • A hematologic disorder
  • Cocaine abuse
  • Cardiac embolism

Atherosclerosis

Although 85% of all strokes are ischemic, and most ischemic strokes are caused by occlusive atherosclerosis of large vessels, most ischemic strokes occur in patients older than 65 years. In patients younger than 55 years, only about 10% of strokes are caused by large-vessel atherosclerotic disease, thus lowering the initial probability that this is the cause of our patient’s stroke.1 Furthermore, our patient’s MRA study showed no carotid artery stenoses, which effectively eliminates this as the cause of his stroke, as the diagnostic sensitivity of MRA for detecting carotid stenosis is approximately 97%.

Cervical arterial dissection

Cervical arterial dissection causes up to 20% of strokes in patients younger than 45 years.2 Dissections usually involve the extracranial portion of the vessel, and involve the internal carotid arteries at least three times as often as the vertebral arteries. In many cases the dissection is preceded by mild neck trauma, which may be as minor as a vigorous cough or turning of the head.

Typical features of dissection include neck pain, headache, and Horner syndrome, followed minutes to hours later by symptoms of ocular or cerebral ischemia, usually a transient ischemic attack rather than a stroke. Neurologic symptoms are most commonly due to thrombosis at the dissection site with distal embolization. Inherited disorders that are associated with increased risk of cervical arterial dissection include Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal-dominant polycystic kidney disease, osteogenesis imperfecta type I, and fibromuscular dysplasia.3 MRA and computed tomographic angiography are the diagnostic tests of choice.

Our patient’s symptoms began suddenly, without a history of trauma or neck pain, making arterial dissection less likely as the cause of his stroke. No dissection was seen on MRA, which also minimizes its likelihood.4

 

 

Hematologic disorders

Many hematologic disorders are associated with ischemic stroke. The disorders most likely to cause ischemic stroke in patients younger than 45 years are antiphospholipid antibody syndrome, sickle cell anemia, and heparin-induced thrombocytopenia,5 which are associated with arterial thrombosis.

Most of the common hereditary hypercoagulable disorders, such as factor V Leiden/activated protein C resistance, the prothrombin gene mutation (G20210A), antithrombin III deficiency, protein C deficiency, and protein S deficiency, typically cause venous thrombosis much more often than they cause arterial thrombosis. Thus, the most typical presentations of stroke in these disorders are cerebral venous thrombosis or paradoxical embolic stroke due to a patent foramen ovale. Antithrombin III deficiency and protein C and protein S deficiency have been associated with arterial thrombosis, but so infrequently that their likelihood in this patient is extremely low.

Clues to the diagnosis of a hypercoagulable state include venous thrombosis in the past, recurrent fetal loss, thrombocytopenia, livedo reticularis, antiphospholipid antibody syndrome, and skin necrosis at the start of oral anticoagulant therapy.

Of importance: the relationship between hereditary hypercoagulable disorders and stroke is considerably weaker than their association with venous thrombosis. Several studies in clinical and general populations have failed to show an independent association between stroke and protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden/activated protein C resistance, or the prothrombin G20210A mutation.6–8 Therefore, most experts do not recommend screening all stroke patients for a hypercoagulable state—only those with a personal or family history of thrombosis or young patients with unexplained stroke.

Our patient does not have historical or clinical features that would suggest a specific hypercoagulable disorder, either acquired (eg, heparin-induced thrombocytopenia) or inherited. A laboratory workup for a hypercoagulable disorder would likely be of little value in determining the cause of his stroke, and even if a hereditary disorder were identified it would be difficult to determine causation. However, if no other explanation for his stroke can be found during the workup, one could consider testing for proteins C and S, antithrombin III, activated protein C resistance (and factor V Leiden if screening for activated protein C resistance is positive), prothrombin G20210A, fibrinogen, homocysteine, D-dimers, and antiphospholipid antibodies.

Cocaine abuse

Another important cause of ischemic stroke is the use of sympathomimetic drugs such as cocaine or amphetamines. The strongest association is with cocaine, which has been seen in case series to cause cerebral vasoconstriction in a dose-dependent manner. Vasoconstriction is also related to a longer duration of cocaine use.9 Several case-control studies have found that the risk of stroke is 4.5 to 6.5 times higher in drug abusers than in controls, and that use of catecholamines or cocaine alone was associated with a significantly increased risk of stroke.10,11

It is certainly advisable to ask about the use of illicit drugs and to send serum and urine samples for appropriate drug screening in young stroke patients, particularly if another cause cannot be found or if drug use is suspected.12

Cardiac embolism

Cardiac embolism is the most likely cause of the stroke in this patient. Up to 20% of the 500,000 strokes that occur annually in the United States are of cardiac embolic origin,13 and the prevalence is even higher in younger patients. In a registry of 428 strokes in patients 15 to 44 years of age, a cardiac source of embolism was the cause in 31.8%.14

Figure 1. Cardiac sources of embolism.
Cardiac causes of embolization (Figure 1) can be categorized as:

 

  • Masses, which include atherosclerotic plaques, cardiac tumors, and infective and noninfective valvular vegetations
  • Passageways for paradoxical embolism, such as a patent foramen ovale or atrial septal defect (Figure 2)
  • Stasis in the left atrium or left ventricle, with a resulting propensity for thrombosis.

Figure 2. Transesophageal echocardiogram in a patient who presented with presyncope (and who had a high-probability ventilation-perfusion scan) shows a clot in transit between the right atrium and left atrium. RA = right atrium, LA = left atrium, RV = right ventricle, LV = left ventricle.
Of these, the most common are left atrial and left ventricular thrombi and aortic atherosclerosis.15

Atrial thrombus is most often seen in patients with atrial fibrillation, mitral stenosis, or dilated cardiomyopathy. Echocardiography of the left atrium in patients with these conditions often reveals spontaneous echo contrast that resembles swirling “smoke,” which is thought to be produced by red blood cell aggregation due to blood stasis. This sign is strongly associated with left atrial thrombi.

Left ventricular thrombosis is one of the most common complications of myocardial infarction and is caused by blood stasis in regions of the ventricle in which the myocardium is hypokinetic or akinetic.

We cannot assume, however, that a potential cardioembolic source seen on echocardiography is the cause of a given patient’s stroke. The evidence proving a causal relationship between most potential cardiac embolic sources and stroke is less than robust. Most of the published data are from nonrandomized studies or case series, and there are no large, prospective studies available to clearly prove that a given cardioembolic source is directly related to embolic stroke.16

This being said, most studies have found high prevalence rates of cardioembolic sources in patients with embolic stroke, which suggests that a causative relationship may exist. However, many of these findings also have a relatively high prevalence among the general population without stroke, raising the possibility that the finding could be incidental and unrelated. Examples are patent foramen ovale, which exists in 27% of adults,17 and aortic arch atheroma, which is common in the elderly.

In the end, when the only potential source of embolism that can be found is in the heart (as is often the case in younger patients), the probability is much greater that it is indeed the cause of the stroke. The lack of direct evidence linking many sources of cardioembolism to stroke emphasizes the need for a thorough investigation of all possible causes of stroke.

 

 

DIAGNOSTIC EVALUATION

2. Which is the best study to evaluate for a cardiac embolic source in this patient?

  • Transthoracic echocardiography (TTE)
  • Transesophageal echocardiography (TEE)
  • Transcranial Doppler ultrasonography
  • Electrocardiography

The study of choice in this patient is TEE. Overall, TEE is better than TTE in identifying a cardiac source of embolism,18,19 mainly because the images are obtained from a probe in the esophagus, which is in close proximity to the heart, so that there is little additional soft tissue and bone between the probe and cardiac structures. In addition, higher-frequency probes can be used. Both of these result in ultrasonographic images with much greater spatial resolution than can be obtained with a transthoracic study.15

In a case series,20 TEE identified a potential cardiac source of embolism in 45 (57%) of 79 patients with cryptogenic stroke, compared with only 12 (15%) with TTE.

The main limitation of TEE is that it does not show the left ventricular apex very well, making an accurate assessment of left ventricular function or identification of a left ventricular apical thrombus much less likely.

In patients who lack evidence of atherosclerotic cerebrovascular disease, specific findings on history or physical examination could increase the chances of identifying an embolic source, such as left ventricular thrombus, on TTE. These findings could include a history of a myocardial infarction, congestive heart failure, left ventricular dysfunction, endocarditis, rheumatic heart disease, a prosthetic valve, or atrial fibrillation or flutter. TTE by itself is considered sufficient for making the diagnosis of mitral stenosis, left ventricular aneurysm, dilated cardiomyopathy, left ventricular thrombus, and mitral valve prolapse with myxomatous degeneration of the leaflets.

However, in patients without signs or symptoms of cardiac disease, the diagnostic value of TTE is significantly less. Several studies have demonstrated that in patients without evidence of cardiac disease, TTE identifies the source of embolism less than 10% of the time.21 Some series even suggest that the yield may be less than 1%.22 TEE has the advantage of being able to diagnose the above disorders and of having a higher sensitivity for identifying potential sources that may be missed by TTE, such as left atrial or left atrial appendage thrombus, aortic arch atheroma, patent foramen ovale, atrial septal aneurysm, or spontaneous echo contrast. It should be remembered, however, that TEE is a semi-invasive procedure that carries the risks of both the procedure and the sedation, eg, bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, and bleeding.23

Further clouding the decision are recent advances in TTE technology, such as contrast TTE with second harmonic imaging, which enhances the ability of TTE to identify potential sources of stroke such as patent foramen ovale nearly to the level of TEE.24

Unfortunately, guidelines from professional societies do not offer assistance on the best diagnostic approach. Current guidelines from the American Heart Association, American College of Cardiology, and American Society of Echocardiography do give echocardiography a class I indication in younger patients (< 45 years old) with cerebrovascular events or older patients (> 45 years old) with stroke without evidence of cerebrovascular disease or other obvious causes. However, there is no official recommendation on whether to choose TTE, TEE, or both studies.16 Given the multiple causes of cardioembolism and the variety of clinical factors that could influence the decision to choose a certain echo study, this decision is appropriately left to the individual physician.

A reasonable, evidence-based diagnostic approach in young stroke patients is to proceed to TEE when routine TTE and electrocardiography are unrevealing.25 In reality, this is the practice followed in most centers, including ours. Although TTE has a lower diagnostic yield in patients without symptoms, it has the advantages of being readily available in most centers, being noninvasive, and providing complementary information to TEE even when TTE does not reveal a potential cause of stroke.

As for the other studies:

Electrocardiography is valuable in identifying potential cardioembolic causes of stroke such as atrial fibrillation, left ventricular aneurysm, or myocardial infarction, but it is insufficient by itself to assess for many other potential sources of cardioembolism.

Transcranial Doppler ultrasonography is very sensitive for detecting patent foramen ovale and other right-to-left shunts that could be sources of cardioembolism. In this test, microbubbles from agitated saline are injected into the venous circulation and are detected in the cerebral arteries after passing through the shunt. It has no utility in identifying the other possibilities discussed above, nor can it discriminate whether these shunts are intra-cardiac or extracardiac.

Case continued

The patient undergoes TTE, which shows normal left ventricular size, wall thickness, and systolic function. His right ventricular function is normal, as are his left and right atrial size. Valvular function is normal, and no right-to-left interatrial shunt is detected with the use of agitated saline contrast.

Figure 3. Left, transesophageal echocardiogram of aortic valve in short-axis view shows papillary fibroelastoma (arrowhead) attached to right coronary cusp. Right, long-axis view.
The patient then undergoes TEE, which reveals a 9- by 8-mm mobile soft-tissue mass attached to the aortic side of the aortic valve at the junction of the right and left coronary cusps (Figure 3). There is trivial aortic insufficiency, and the rest of the aorta appears normal. This lesion is consistent with a valvular papillary fibroelastoma.

 

 

MANAGEMENT

3. Which is the most appropriate way to manage the lesion?

  • Surgical resection
  • Periodic echocardiographic follow-up
  • Anticoagulation and periodic echocardiographic follow-up

Cardiac papillary fibroelastomas are rare benign primary tumors of the heart. The true incidence is unknown because, when small, they can be asymptomatic and easily overlooked on gross examination. In adults, they are the second most common primary cardiac tumors, next to atrial myxoma.26

Figure 4. A, papillary fibroelastomas are composed of fine and coarse branching fingerlike projections that usually arise on valve surfaces. B, the papillary fronds are avascular and composed of dense collagenous cores covered by a single layer of endothelium (hematoxylin and eosin). C, a Movat pentachrome stain shows elastic fibers within the fibrous core (elastin—black; collagen—yellow).
These tumors primarily affect the valves (most often the aortic valve), and consist of a small, highly papillary, avascular tumor covered by a single layer of endothelium, containing variable amounts of fine elastic fibers arranged around a central hyaline stroma (Figure 4).27 Most of the tumors are sessile, while a few are attached to the valve by a short stalk.

The histogenesis is not known, but the mean age at which they are detected is approximately 60 years, and most of the patients are men, likely because most of these tumors are found incidentally during echocardiography, open heart surgery, or autopsy.28

Most patients with cardiac papillary fibroelastomas have no symptoms; however, those who do have symptoms usually experience valve obstruction or embolization of tumor fragments, leading to stroke, myocardial infarction, or sudden death. Further increasing the risk of embolism, thrombus has been reported on the surface of some tumors, supporting the use of anticoagulation in patients who have experienced embolic phenomena.29

A case review of 725 patients with these tumors27 found that tumor mobility and location on the aortic valve were univariate predictors of tumor-related death and of nonfatal embolism. The only independent predictor of tumor-related death or nonfatal embolization was tumor mobility.

Surgical resection of the tumor is curative, and no recurrences have been reported, although the longest follow-up period has been 11 years.

Although no data exist to support the practice, patients with nonmobile or nonaortic valve tumors could be managed with anticoagulation and periodic echocardiographic follow-up until the tumor becomes mobile or symptomatic, but such a conservative strategy would seem inappropriate for our patient. His tumor is both mobile and located on the aortic valve, putting him at risk of death, and he has already experienced an embolic complication. Therefore, his lesion should be surgically resected.

Case continued

The patient receives anticoagulation therapy with subcutaneous enoxaparin (Lovenox) and warfarin (Coumadin). He undergoes successful surgical resection of the tumor without complication and is discharged to home on hospital day 5.

TAKE-HOME POINTS

The potential causes of stroke in patients younger than age 45 differ significantly from those in older patients. Cardiac embolism is the most frequent cause of stroke in young patients and is most often from left atrial or ventricular thrombus or from aortic atheroma.

In young patients, TEE is superior to TTE in identifying a specific source of cardiac embolism, particularly when clues from the history or physical examination are lacking and the preliminary diagnostic workup fails to identify the cause of the stroke.

Our patient’s history, physical examination, MRI, MRA, electrocardiography, and TTE all failed to disclose a probable cause of his stroke. Appropriately, TEE was performed, which confirmed the diagnosis of cardiac papillary fibroelastoma, a rare and benign primary tumor of the heart with the potential for disastrous consequences.

References
  1. Bogousslavsky J, Van Melle G, Regli F. The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke. Stroke 1988; 19:10831092.
  2. Bogousslavsky J, Pierre P. Ischemic stroke in patients under age 45. Neurol Clin 1992; 10:113124.
  3. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001; 344:898906.
  4. Thanvi B, Munshi SK, Dawson SL, Ribinson TG. Carotid and vertebral artery dissection syndromes. Postgrad Med J 2005; 81:383388.
  5. Levine SR. Hypercoagulable states and stroke: a selective review. CNS Spectr 2005; 10:567578.
  6. Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100:310.
  7. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332:912917.
  8. Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001; 32:17931799.
  9. Kaufman MJ, Levin JM, Ross MH, et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 1998; 279:376380.
  10. Kaku DA, Lowenstein DH. Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 1990; 113:821827.
  11. Petitti DB, Sidney S, Quesenberry C, Bernstein A. Stroke and cocaine or amphetamine use. Epidemiology 1998; 9:596600.
  12. Bruno A. Cerebrovascular complications of alcohol and sympathomimetic drug abuse. Curr Neurol Neurosci Rep 2003; 3:4045.
  13. Cardiogenic brain embolism. The second report of the Cerebral Embolism Task Force. Arch Neurol 1989; 46:727743.
  14. Kittner SJ, Stern BJ, Wozniak M, et al. Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Neurology 1998; 50:890894.
  15. Manning WJ. Role of transesophageal echocardiography in the management of thromboembolic stroke. Am J Cardiol 1997; 80 4C:19D28D.
  16. Cheitlin MD, Armstrong WF, Aurigemma GP, et al American College of Cardiology; American Heart Association; American Society of Echocardiography. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation 2003; 108:11461162.
  17. Kizer JR, Devereux RB. Clinical practice. Patent foramen ovale in young adults with unexplained stroke. N Engl J Med 2005; 353:23612372.
  18. Pearson AC. Transthoracic echocardiography versus transesophageal echocardiography in detecting cardiac sources of embolism. Echocardiography 1993; 10:397403.
  19. DeRook FA, Comess KA, Albers GW, Popp RL. Transesophageal echocardiography in the evaluation of stroke. Ann Intern Med 1992; 117:922932.
  20. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17:6672.
  21. Rahmatullah AF, Rahko PS, Stein JH. Transesophageal echocardiography for the evaluation and management of patients with cerebral ischemia. Clin Cardiol 1999; 22:391396.
  22. Come PC, Riley MF, Bivas NK. Roles of echocardiography and arrhythmia monitoring in the evaluation of patients with suspected systemic embolism. Ann Neurol 1983; 13:527531.
  23. Daniel WG, Erbel R, Kasper W, et al. Safety of transesophageal echocardiography. A multicenter survey of 10,419 examinations. Circulation 1991; 83:817821.
  24. Souteyrand G, Motreff P, Lusson JR, et al. Comparison of transthoracic echocardiography using second harmonic imaging, transcranial Doppler and transesophageal echocardiography for the detection of patent foramen ovale in stroke patients. Eur J Echocardiogr 2006; 7:147154.
  25. Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke 2006; 37:859864.
  26. Burke A, Virami R. Tumors of the heart and great vessels. Atlas of Tumor Pathology, 1996, 3rd Series, Fascicle 16. Washington, DC: Armed Forces Institute of Pathology.
  27. Gowda RM, Khan IA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart J 2003; 146:404410.
  28. Edwards FH, Hale D, Cohen A, Thompson L, Pezzella AT, Virmani R. Primary cardiac valve tumors. Ann Thorac Surg 1991; 52:11271131.
  29. Joffe II, Jacobs LE, Owen AN, Ioli A, Kotler MN. Rapid development of a papillary fibroelastoma with associated thrombus: the role of transthoracic and transesophageal echocardiography. Echocardiography 1997; 14:287292.
Article PDF
Author and Disclosure Information

Matthew A. Kaminski, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Carmela D. Tan, MD
Department of Anatomic Pathology, Cleveland Clinic

Arman T. Askari, MD
Associate Director, Cardiovascular Medicine Training Program, Department of Cardiovascular Medicine, Cleveland Clinic

Address: Arman T. Askari, MD, Department of Cardiovascular Medicine, F15, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Publications
Topics
Page Number
145-152
Sections
Author and Disclosure Information

Matthew A. Kaminski, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Carmela D. Tan, MD
Department of Anatomic Pathology, Cleveland Clinic

Arman T. Askari, MD
Associate Director, Cardiovascular Medicine Training Program, Department of Cardiovascular Medicine, Cleveland Clinic

Address: Arman T. Askari, MD, Department of Cardiovascular Medicine, F15, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Author and Disclosure Information

Matthew A. Kaminski, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Carmela D. Tan, MD
Department of Anatomic Pathology, Cleveland Clinic

Arman T. Askari, MD
Associate Director, Cardiovascular Medicine Training Program, Department of Cardiovascular Medicine, Cleveland Clinic

Address: Arman T. Askari, MD, Department of Cardiovascular Medicine, F15, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Article PDF
Article PDF

A 42-year-old man was working at his computer when he suddenly became disoriented and lightheaded, had difficulty concentrating, and could not move his right arm. He could walk without difficulty, but he had a tingling sensation in his right leg. He did not lose consciousness or have any associated palpitations, chest pain, shortness of breath, nausea, vomiting, headaches, or visual changes.

He called 911, and an ambulance arrived 15 minutes later. By that time his symptoms had started to resolve. Now, in the emergency department, his only residual symptom is mild numbness of his right arm and shoulder.

Until now he has been healthy except for a history of dyslipidemia. He takes no prescription or over-the-counter medications and has no drug allergies. He has smoked one pack of cigarettes daily for the past 28 years and also smokes marijuana several times each month. He drinks alcohol occasionally. His family has no history of stroke, premature coronary artery disease, or sudden cardiac death.

INITIAL EVALUATION

His heart rate is 88 beats per minute, blood pressure 142/82 mm Hg, and blood oxygen saturation 98% while breathing room air. He is alert and in no acute distress and answers questions appropriately.

His breathing sounds are normal, without crackles or wheezes. His heart has normal first and second sounds, a normal rate and rhythm, and no extra sounds or murmurs. His abdomen is normal. His extremities are warm and well perfused with normal peripheral pulses and no edema.

On neurologic examination, his cranial nerves and visual fields are normal, and his strength is normal in all muscle groups except for the right upper arm, which is slightly weaker than the left when tested against resistance. Reflexes and response to light touch and pinprick are normal.

His serum chemistry levels, renal function, and blood counts are normal. His total cholesterol level is 155 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, low-density lipoprotein cholesterol 108 mg/dL, and triglycerides 1,286 mg/dL. Electrocardiography is normal with sinus rhythm at a rate of 74.

Magnetic resonance imaging (MRI) of the head and neck with magnetic resonance angiography (MRA) of the intracranial and extracranial vessels is performed. Diffusion-weighted images show a hyperintense lesion in the left insular cortex, consistent with an infarct in the distribution of a branch of the left middle cerebral artery. There is no intracranial hemorrhage. All intracranial and extracranial major vessels are patent, and no stenoses are seen.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s stroke?

  • Vertebral or carotid atherosclerosis
  • Cervical arterial dissection
  • A hematologic disorder
  • Cocaine abuse
  • Cardiac embolism

Atherosclerosis

Although 85% of all strokes are ischemic, and most ischemic strokes are caused by occlusive atherosclerosis of large vessels, most ischemic strokes occur in patients older than 65 years. In patients younger than 55 years, only about 10% of strokes are caused by large-vessel atherosclerotic disease, thus lowering the initial probability that this is the cause of our patient’s stroke.1 Furthermore, our patient’s MRA study showed no carotid artery stenoses, which effectively eliminates this as the cause of his stroke, as the diagnostic sensitivity of MRA for detecting carotid stenosis is approximately 97%.

Cervical arterial dissection

Cervical arterial dissection causes up to 20% of strokes in patients younger than 45 years.2 Dissections usually involve the extracranial portion of the vessel, and involve the internal carotid arteries at least three times as often as the vertebral arteries. In many cases the dissection is preceded by mild neck trauma, which may be as minor as a vigorous cough or turning of the head.

Typical features of dissection include neck pain, headache, and Horner syndrome, followed minutes to hours later by symptoms of ocular or cerebral ischemia, usually a transient ischemic attack rather than a stroke. Neurologic symptoms are most commonly due to thrombosis at the dissection site with distal embolization. Inherited disorders that are associated with increased risk of cervical arterial dissection include Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal-dominant polycystic kidney disease, osteogenesis imperfecta type I, and fibromuscular dysplasia.3 MRA and computed tomographic angiography are the diagnostic tests of choice.

Our patient’s symptoms began suddenly, without a history of trauma or neck pain, making arterial dissection less likely as the cause of his stroke. No dissection was seen on MRA, which also minimizes its likelihood.4

 

 

Hematologic disorders

Many hematologic disorders are associated with ischemic stroke. The disorders most likely to cause ischemic stroke in patients younger than 45 years are antiphospholipid antibody syndrome, sickle cell anemia, and heparin-induced thrombocytopenia,5 which are associated with arterial thrombosis.

Most of the common hereditary hypercoagulable disorders, such as factor V Leiden/activated protein C resistance, the prothrombin gene mutation (G20210A), antithrombin III deficiency, protein C deficiency, and protein S deficiency, typically cause venous thrombosis much more often than they cause arterial thrombosis. Thus, the most typical presentations of stroke in these disorders are cerebral venous thrombosis or paradoxical embolic stroke due to a patent foramen ovale. Antithrombin III deficiency and protein C and protein S deficiency have been associated with arterial thrombosis, but so infrequently that their likelihood in this patient is extremely low.

Clues to the diagnosis of a hypercoagulable state include venous thrombosis in the past, recurrent fetal loss, thrombocytopenia, livedo reticularis, antiphospholipid antibody syndrome, and skin necrosis at the start of oral anticoagulant therapy.

Of importance: the relationship between hereditary hypercoagulable disorders and stroke is considerably weaker than their association with venous thrombosis. Several studies in clinical and general populations have failed to show an independent association between stroke and protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden/activated protein C resistance, or the prothrombin G20210A mutation.6–8 Therefore, most experts do not recommend screening all stroke patients for a hypercoagulable state—only those with a personal or family history of thrombosis or young patients with unexplained stroke.

Our patient does not have historical or clinical features that would suggest a specific hypercoagulable disorder, either acquired (eg, heparin-induced thrombocytopenia) or inherited. A laboratory workup for a hypercoagulable disorder would likely be of little value in determining the cause of his stroke, and even if a hereditary disorder were identified it would be difficult to determine causation. However, if no other explanation for his stroke can be found during the workup, one could consider testing for proteins C and S, antithrombin III, activated protein C resistance (and factor V Leiden if screening for activated protein C resistance is positive), prothrombin G20210A, fibrinogen, homocysteine, D-dimers, and antiphospholipid antibodies.

Cocaine abuse

Another important cause of ischemic stroke is the use of sympathomimetic drugs such as cocaine or amphetamines. The strongest association is with cocaine, which has been seen in case series to cause cerebral vasoconstriction in a dose-dependent manner. Vasoconstriction is also related to a longer duration of cocaine use.9 Several case-control studies have found that the risk of stroke is 4.5 to 6.5 times higher in drug abusers than in controls, and that use of catecholamines or cocaine alone was associated with a significantly increased risk of stroke.10,11

It is certainly advisable to ask about the use of illicit drugs and to send serum and urine samples for appropriate drug screening in young stroke patients, particularly if another cause cannot be found or if drug use is suspected.12

Cardiac embolism

Cardiac embolism is the most likely cause of the stroke in this patient. Up to 20% of the 500,000 strokes that occur annually in the United States are of cardiac embolic origin,13 and the prevalence is even higher in younger patients. In a registry of 428 strokes in patients 15 to 44 years of age, a cardiac source of embolism was the cause in 31.8%.14

Figure 1. Cardiac sources of embolism.
Cardiac causes of embolization (Figure 1) can be categorized as:

 

  • Masses, which include atherosclerotic plaques, cardiac tumors, and infective and noninfective valvular vegetations
  • Passageways for paradoxical embolism, such as a patent foramen ovale or atrial septal defect (Figure 2)
  • Stasis in the left atrium or left ventricle, with a resulting propensity for thrombosis.

Figure 2. Transesophageal echocardiogram in a patient who presented with presyncope (and who had a high-probability ventilation-perfusion scan) shows a clot in transit between the right atrium and left atrium. RA = right atrium, LA = left atrium, RV = right ventricle, LV = left ventricle.
Of these, the most common are left atrial and left ventricular thrombi and aortic atherosclerosis.15

Atrial thrombus is most often seen in patients with atrial fibrillation, mitral stenosis, or dilated cardiomyopathy. Echocardiography of the left atrium in patients with these conditions often reveals spontaneous echo contrast that resembles swirling “smoke,” which is thought to be produced by red blood cell aggregation due to blood stasis. This sign is strongly associated with left atrial thrombi.

Left ventricular thrombosis is one of the most common complications of myocardial infarction and is caused by blood stasis in regions of the ventricle in which the myocardium is hypokinetic or akinetic.

We cannot assume, however, that a potential cardioembolic source seen on echocardiography is the cause of a given patient’s stroke. The evidence proving a causal relationship between most potential cardiac embolic sources and stroke is less than robust. Most of the published data are from nonrandomized studies or case series, and there are no large, prospective studies available to clearly prove that a given cardioembolic source is directly related to embolic stroke.16

This being said, most studies have found high prevalence rates of cardioembolic sources in patients with embolic stroke, which suggests that a causative relationship may exist. However, many of these findings also have a relatively high prevalence among the general population without stroke, raising the possibility that the finding could be incidental and unrelated. Examples are patent foramen ovale, which exists in 27% of adults,17 and aortic arch atheroma, which is common in the elderly.

In the end, when the only potential source of embolism that can be found is in the heart (as is often the case in younger patients), the probability is much greater that it is indeed the cause of the stroke. The lack of direct evidence linking many sources of cardioembolism to stroke emphasizes the need for a thorough investigation of all possible causes of stroke.

 

 

DIAGNOSTIC EVALUATION

2. Which is the best study to evaluate for a cardiac embolic source in this patient?

  • Transthoracic echocardiography (TTE)
  • Transesophageal echocardiography (TEE)
  • Transcranial Doppler ultrasonography
  • Electrocardiography

The study of choice in this patient is TEE. Overall, TEE is better than TTE in identifying a cardiac source of embolism,18,19 mainly because the images are obtained from a probe in the esophagus, which is in close proximity to the heart, so that there is little additional soft tissue and bone between the probe and cardiac structures. In addition, higher-frequency probes can be used. Both of these result in ultrasonographic images with much greater spatial resolution than can be obtained with a transthoracic study.15

In a case series,20 TEE identified a potential cardiac source of embolism in 45 (57%) of 79 patients with cryptogenic stroke, compared with only 12 (15%) with TTE.

The main limitation of TEE is that it does not show the left ventricular apex very well, making an accurate assessment of left ventricular function or identification of a left ventricular apical thrombus much less likely.

In patients who lack evidence of atherosclerotic cerebrovascular disease, specific findings on history or physical examination could increase the chances of identifying an embolic source, such as left ventricular thrombus, on TTE. These findings could include a history of a myocardial infarction, congestive heart failure, left ventricular dysfunction, endocarditis, rheumatic heart disease, a prosthetic valve, or atrial fibrillation or flutter. TTE by itself is considered sufficient for making the diagnosis of mitral stenosis, left ventricular aneurysm, dilated cardiomyopathy, left ventricular thrombus, and mitral valve prolapse with myxomatous degeneration of the leaflets.

However, in patients without signs or symptoms of cardiac disease, the diagnostic value of TTE is significantly less. Several studies have demonstrated that in patients without evidence of cardiac disease, TTE identifies the source of embolism less than 10% of the time.21 Some series even suggest that the yield may be less than 1%.22 TEE has the advantage of being able to diagnose the above disorders and of having a higher sensitivity for identifying potential sources that may be missed by TTE, such as left atrial or left atrial appendage thrombus, aortic arch atheroma, patent foramen ovale, atrial septal aneurysm, or spontaneous echo contrast. It should be remembered, however, that TEE is a semi-invasive procedure that carries the risks of both the procedure and the sedation, eg, bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, and bleeding.23

Further clouding the decision are recent advances in TTE technology, such as contrast TTE with second harmonic imaging, which enhances the ability of TTE to identify potential sources of stroke such as patent foramen ovale nearly to the level of TEE.24

Unfortunately, guidelines from professional societies do not offer assistance on the best diagnostic approach. Current guidelines from the American Heart Association, American College of Cardiology, and American Society of Echocardiography do give echocardiography a class I indication in younger patients (< 45 years old) with cerebrovascular events or older patients (> 45 years old) with stroke without evidence of cerebrovascular disease or other obvious causes. However, there is no official recommendation on whether to choose TTE, TEE, or both studies.16 Given the multiple causes of cardioembolism and the variety of clinical factors that could influence the decision to choose a certain echo study, this decision is appropriately left to the individual physician.

A reasonable, evidence-based diagnostic approach in young stroke patients is to proceed to TEE when routine TTE and electrocardiography are unrevealing.25 In reality, this is the practice followed in most centers, including ours. Although TTE has a lower diagnostic yield in patients without symptoms, it has the advantages of being readily available in most centers, being noninvasive, and providing complementary information to TEE even when TTE does not reveal a potential cause of stroke.

As for the other studies:

Electrocardiography is valuable in identifying potential cardioembolic causes of stroke such as atrial fibrillation, left ventricular aneurysm, or myocardial infarction, but it is insufficient by itself to assess for many other potential sources of cardioembolism.

Transcranial Doppler ultrasonography is very sensitive for detecting patent foramen ovale and other right-to-left shunts that could be sources of cardioembolism. In this test, microbubbles from agitated saline are injected into the venous circulation and are detected in the cerebral arteries after passing through the shunt. It has no utility in identifying the other possibilities discussed above, nor can it discriminate whether these shunts are intra-cardiac or extracardiac.

Case continued

The patient undergoes TTE, which shows normal left ventricular size, wall thickness, and systolic function. His right ventricular function is normal, as are his left and right atrial size. Valvular function is normal, and no right-to-left interatrial shunt is detected with the use of agitated saline contrast.

Figure 3. Left, transesophageal echocardiogram of aortic valve in short-axis view shows papillary fibroelastoma (arrowhead) attached to right coronary cusp. Right, long-axis view.
The patient then undergoes TEE, which reveals a 9- by 8-mm mobile soft-tissue mass attached to the aortic side of the aortic valve at the junction of the right and left coronary cusps (Figure 3). There is trivial aortic insufficiency, and the rest of the aorta appears normal. This lesion is consistent with a valvular papillary fibroelastoma.

 

 

MANAGEMENT

3. Which is the most appropriate way to manage the lesion?

  • Surgical resection
  • Periodic echocardiographic follow-up
  • Anticoagulation and periodic echocardiographic follow-up

Cardiac papillary fibroelastomas are rare benign primary tumors of the heart. The true incidence is unknown because, when small, they can be asymptomatic and easily overlooked on gross examination. In adults, they are the second most common primary cardiac tumors, next to atrial myxoma.26

Figure 4. A, papillary fibroelastomas are composed of fine and coarse branching fingerlike projections that usually arise on valve surfaces. B, the papillary fronds are avascular and composed of dense collagenous cores covered by a single layer of endothelium (hematoxylin and eosin). C, a Movat pentachrome stain shows elastic fibers within the fibrous core (elastin—black; collagen—yellow).
These tumors primarily affect the valves (most often the aortic valve), and consist of a small, highly papillary, avascular tumor covered by a single layer of endothelium, containing variable amounts of fine elastic fibers arranged around a central hyaline stroma (Figure 4).27 Most of the tumors are sessile, while a few are attached to the valve by a short stalk.

The histogenesis is not known, but the mean age at which they are detected is approximately 60 years, and most of the patients are men, likely because most of these tumors are found incidentally during echocardiography, open heart surgery, or autopsy.28

Most patients with cardiac papillary fibroelastomas have no symptoms; however, those who do have symptoms usually experience valve obstruction or embolization of tumor fragments, leading to stroke, myocardial infarction, or sudden death. Further increasing the risk of embolism, thrombus has been reported on the surface of some tumors, supporting the use of anticoagulation in patients who have experienced embolic phenomena.29

A case review of 725 patients with these tumors27 found that tumor mobility and location on the aortic valve were univariate predictors of tumor-related death and of nonfatal embolism. The only independent predictor of tumor-related death or nonfatal embolization was tumor mobility.

Surgical resection of the tumor is curative, and no recurrences have been reported, although the longest follow-up period has been 11 years.

Although no data exist to support the practice, patients with nonmobile or nonaortic valve tumors could be managed with anticoagulation and periodic echocardiographic follow-up until the tumor becomes mobile or symptomatic, but such a conservative strategy would seem inappropriate for our patient. His tumor is both mobile and located on the aortic valve, putting him at risk of death, and he has already experienced an embolic complication. Therefore, his lesion should be surgically resected.

Case continued

The patient receives anticoagulation therapy with subcutaneous enoxaparin (Lovenox) and warfarin (Coumadin). He undergoes successful surgical resection of the tumor without complication and is discharged to home on hospital day 5.

TAKE-HOME POINTS

The potential causes of stroke in patients younger than age 45 differ significantly from those in older patients. Cardiac embolism is the most frequent cause of stroke in young patients and is most often from left atrial or ventricular thrombus or from aortic atheroma.

In young patients, TEE is superior to TTE in identifying a specific source of cardiac embolism, particularly when clues from the history or physical examination are lacking and the preliminary diagnostic workup fails to identify the cause of the stroke.

Our patient’s history, physical examination, MRI, MRA, electrocardiography, and TTE all failed to disclose a probable cause of his stroke. Appropriately, TEE was performed, which confirmed the diagnosis of cardiac papillary fibroelastoma, a rare and benign primary tumor of the heart with the potential for disastrous consequences.

A 42-year-old man was working at his computer when he suddenly became disoriented and lightheaded, had difficulty concentrating, and could not move his right arm. He could walk without difficulty, but he had a tingling sensation in his right leg. He did not lose consciousness or have any associated palpitations, chest pain, shortness of breath, nausea, vomiting, headaches, or visual changes.

He called 911, and an ambulance arrived 15 minutes later. By that time his symptoms had started to resolve. Now, in the emergency department, his only residual symptom is mild numbness of his right arm and shoulder.

Until now he has been healthy except for a history of dyslipidemia. He takes no prescription or over-the-counter medications and has no drug allergies. He has smoked one pack of cigarettes daily for the past 28 years and also smokes marijuana several times each month. He drinks alcohol occasionally. His family has no history of stroke, premature coronary artery disease, or sudden cardiac death.

INITIAL EVALUATION

His heart rate is 88 beats per minute, blood pressure 142/82 mm Hg, and blood oxygen saturation 98% while breathing room air. He is alert and in no acute distress and answers questions appropriately.

His breathing sounds are normal, without crackles or wheezes. His heart has normal first and second sounds, a normal rate and rhythm, and no extra sounds or murmurs. His abdomen is normal. His extremities are warm and well perfused with normal peripheral pulses and no edema.

On neurologic examination, his cranial nerves and visual fields are normal, and his strength is normal in all muscle groups except for the right upper arm, which is slightly weaker than the left when tested against resistance. Reflexes and response to light touch and pinprick are normal.

His serum chemistry levels, renal function, and blood counts are normal. His total cholesterol level is 155 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, low-density lipoprotein cholesterol 108 mg/dL, and triglycerides 1,286 mg/dL. Electrocardiography is normal with sinus rhythm at a rate of 74.

Magnetic resonance imaging (MRI) of the head and neck with magnetic resonance angiography (MRA) of the intracranial and extracranial vessels is performed. Diffusion-weighted images show a hyperintense lesion in the left insular cortex, consistent with an infarct in the distribution of a branch of the left middle cerebral artery. There is no intracranial hemorrhage. All intracranial and extracranial major vessels are patent, and no stenoses are seen.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s stroke?

  • Vertebral or carotid atherosclerosis
  • Cervical arterial dissection
  • A hematologic disorder
  • Cocaine abuse
  • Cardiac embolism

Atherosclerosis

Although 85% of all strokes are ischemic, and most ischemic strokes are caused by occlusive atherosclerosis of large vessels, most ischemic strokes occur in patients older than 65 years. In patients younger than 55 years, only about 10% of strokes are caused by large-vessel atherosclerotic disease, thus lowering the initial probability that this is the cause of our patient’s stroke.1 Furthermore, our patient’s MRA study showed no carotid artery stenoses, which effectively eliminates this as the cause of his stroke, as the diagnostic sensitivity of MRA for detecting carotid stenosis is approximately 97%.

Cervical arterial dissection

Cervical arterial dissection causes up to 20% of strokes in patients younger than 45 years.2 Dissections usually involve the extracranial portion of the vessel, and involve the internal carotid arteries at least three times as often as the vertebral arteries. In many cases the dissection is preceded by mild neck trauma, which may be as minor as a vigorous cough or turning of the head.

Typical features of dissection include neck pain, headache, and Horner syndrome, followed minutes to hours later by symptoms of ocular or cerebral ischemia, usually a transient ischemic attack rather than a stroke. Neurologic symptoms are most commonly due to thrombosis at the dissection site with distal embolization. Inherited disorders that are associated with increased risk of cervical arterial dissection include Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal-dominant polycystic kidney disease, osteogenesis imperfecta type I, and fibromuscular dysplasia.3 MRA and computed tomographic angiography are the diagnostic tests of choice.

Our patient’s symptoms began suddenly, without a history of trauma or neck pain, making arterial dissection less likely as the cause of his stroke. No dissection was seen on MRA, which also minimizes its likelihood.4

 

 

Hematologic disorders

Many hematologic disorders are associated with ischemic stroke. The disorders most likely to cause ischemic stroke in patients younger than 45 years are antiphospholipid antibody syndrome, sickle cell anemia, and heparin-induced thrombocytopenia,5 which are associated with arterial thrombosis.

Most of the common hereditary hypercoagulable disorders, such as factor V Leiden/activated protein C resistance, the prothrombin gene mutation (G20210A), antithrombin III deficiency, protein C deficiency, and protein S deficiency, typically cause venous thrombosis much more often than they cause arterial thrombosis. Thus, the most typical presentations of stroke in these disorders are cerebral venous thrombosis or paradoxical embolic stroke due to a patent foramen ovale. Antithrombin III deficiency and protein C and protein S deficiency have been associated with arterial thrombosis, but so infrequently that their likelihood in this patient is extremely low.

Clues to the diagnosis of a hypercoagulable state include venous thrombosis in the past, recurrent fetal loss, thrombocytopenia, livedo reticularis, antiphospholipid antibody syndrome, and skin necrosis at the start of oral anticoagulant therapy.

Of importance: the relationship between hereditary hypercoagulable disorders and stroke is considerably weaker than their association with venous thrombosis. Several studies in clinical and general populations have failed to show an independent association between stroke and protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden/activated protein C resistance, or the prothrombin G20210A mutation.6–8 Therefore, most experts do not recommend screening all stroke patients for a hypercoagulable state—only those with a personal or family history of thrombosis or young patients with unexplained stroke.

Our patient does not have historical or clinical features that would suggest a specific hypercoagulable disorder, either acquired (eg, heparin-induced thrombocytopenia) or inherited. A laboratory workup for a hypercoagulable disorder would likely be of little value in determining the cause of his stroke, and even if a hereditary disorder were identified it would be difficult to determine causation. However, if no other explanation for his stroke can be found during the workup, one could consider testing for proteins C and S, antithrombin III, activated protein C resistance (and factor V Leiden if screening for activated protein C resistance is positive), prothrombin G20210A, fibrinogen, homocysteine, D-dimers, and antiphospholipid antibodies.

Cocaine abuse

Another important cause of ischemic stroke is the use of sympathomimetic drugs such as cocaine or amphetamines. The strongest association is with cocaine, which has been seen in case series to cause cerebral vasoconstriction in a dose-dependent manner. Vasoconstriction is also related to a longer duration of cocaine use.9 Several case-control studies have found that the risk of stroke is 4.5 to 6.5 times higher in drug abusers than in controls, and that use of catecholamines or cocaine alone was associated with a significantly increased risk of stroke.10,11

It is certainly advisable to ask about the use of illicit drugs and to send serum and urine samples for appropriate drug screening in young stroke patients, particularly if another cause cannot be found or if drug use is suspected.12

Cardiac embolism

Cardiac embolism is the most likely cause of the stroke in this patient. Up to 20% of the 500,000 strokes that occur annually in the United States are of cardiac embolic origin,13 and the prevalence is even higher in younger patients. In a registry of 428 strokes in patients 15 to 44 years of age, a cardiac source of embolism was the cause in 31.8%.14

Figure 1. Cardiac sources of embolism.
Cardiac causes of embolization (Figure 1) can be categorized as:

 

  • Masses, which include atherosclerotic plaques, cardiac tumors, and infective and noninfective valvular vegetations
  • Passageways for paradoxical embolism, such as a patent foramen ovale or atrial septal defect (Figure 2)
  • Stasis in the left atrium or left ventricle, with a resulting propensity for thrombosis.

Figure 2. Transesophageal echocardiogram in a patient who presented with presyncope (and who had a high-probability ventilation-perfusion scan) shows a clot in transit between the right atrium and left atrium. RA = right atrium, LA = left atrium, RV = right ventricle, LV = left ventricle.
Of these, the most common are left atrial and left ventricular thrombi and aortic atherosclerosis.15

Atrial thrombus is most often seen in patients with atrial fibrillation, mitral stenosis, or dilated cardiomyopathy. Echocardiography of the left atrium in patients with these conditions often reveals spontaneous echo contrast that resembles swirling “smoke,” which is thought to be produced by red blood cell aggregation due to blood stasis. This sign is strongly associated with left atrial thrombi.

Left ventricular thrombosis is one of the most common complications of myocardial infarction and is caused by blood stasis in regions of the ventricle in which the myocardium is hypokinetic or akinetic.

We cannot assume, however, that a potential cardioembolic source seen on echocardiography is the cause of a given patient’s stroke. The evidence proving a causal relationship between most potential cardiac embolic sources and stroke is less than robust. Most of the published data are from nonrandomized studies or case series, and there are no large, prospective studies available to clearly prove that a given cardioembolic source is directly related to embolic stroke.16

This being said, most studies have found high prevalence rates of cardioembolic sources in patients with embolic stroke, which suggests that a causative relationship may exist. However, many of these findings also have a relatively high prevalence among the general population without stroke, raising the possibility that the finding could be incidental and unrelated. Examples are patent foramen ovale, which exists in 27% of adults,17 and aortic arch atheroma, which is common in the elderly.

In the end, when the only potential source of embolism that can be found is in the heart (as is often the case in younger patients), the probability is much greater that it is indeed the cause of the stroke. The lack of direct evidence linking many sources of cardioembolism to stroke emphasizes the need for a thorough investigation of all possible causes of stroke.

 

 

DIAGNOSTIC EVALUATION

2. Which is the best study to evaluate for a cardiac embolic source in this patient?

  • Transthoracic echocardiography (TTE)
  • Transesophageal echocardiography (TEE)
  • Transcranial Doppler ultrasonography
  • Electrocardiography

The study of choice in this patient is TEE. Overall, TEE is better than TTE in identifying a cardiac source of embolism,18,19 mainly because the images are obtained from a probe in the esophagus, which is in close proximity to the heart, so that there is little additional soft tissue and bone between the probe and cardiac structures. In addition, higher-frequency probes can be used. Both of these result in ultrasonographic images with much greater spatial resolution than can be obtained with a transthoracic study.15

In a case series,20 TEE identified a potential cardiac source of embolism in 45 (57%) of 79 patients with cryptogenic stroke, compared with only 12 (15%) with TTE.

The main limitation of TEE is that it does not show the left ventricular apex very well, making an accurate assessment of left ventricular function or identification of a left ventricular apical thrombus much less likely.

In patients who lack evidence of atherosclerotic cerebrovascular disease, specific findings on history or physical examination could increase the chances of identifying an embolic source, such as left ventricular thrombus, on TTE. These findings could include a history of a myocardial infarction, congestive heart failure, left ventricular dysfunction, endocarditis, rheumatic heart disease, a prosthetic valve, or atrial fibrillation or flutter. TTE by itself is considered sufficient for making the diagnosis of mitral stenosis, left ventricular aneurysm, dilated cardiomyopathy, left ventricular thrombus, and mitral valve prolapse with myxomatous degeneration of the leaflets.

However, in patients without signs or symptoms of cardiac disease, the diagnostic value of TTE is significantly less. Several studies have demonstrated that in patients without evidence of cardiac disease, TTE identifies the source of embolism less than 10% of the time.21 Some series even suggest that the yield may be less than 1%.22 TEE has the advantage of being able to diagnose the above disorders and of having a higher sensitivity for identifying potential sources that may be missed by TTE, such as left atrial or left atrial appendage thrombus, aortic arch atheroma, patent foramen ovale, atrial septal aneurysm, or spontaneous echo contrast. It should be remembered, however, that TEE is a semi-invasive procedure that carries the risks of both the procedure and the sedation, eg, bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, and bleeding.23

Further clouding the decision are recent advances in TTE technology, such as contrast TTE with second harmonic imaging, which enhances the ability of TTE to identify potential sources of stroke such as patent foramen ovale nearly to the level of TEE.24

Unfortunately, guidelines from professional societies do not offer assistance on the best diagnostic approach. Current guidelines from the American Heart Association, American College of Cardiology, and American Society of Echocardiography do give echocardiography a class I indication in younger patients (< 45 years old) with cerebrovascular events or older patients (> 45 years old) with stroke without evidence of cerebrovascular disease or other obvious causes. However, there is no official recommendation on whether to choose TTE, TEE, or both studies.16 Given the multiple causes of cardioembolism and the variety of clinical factors that could influence the decision to choose a certain echo study, this decision is appropriately left to the individual physician.

A reasonable, evidence-based diagnostic approach in young stroke patients is to proceed to TEE when routine TTE and electrocardiography are unrevealing.25 In reality, this is the practice followed in most centers, including ours. Although TTE has a lower diagnostic yield in patients without symptoms, it has the advantages of being readily available in most centers, being noninvasive, and providing complementary information to TEE even when TTE does not reveal a potential cause of stroke.

As for the other studies:

Electrocardiography is valuable in identifying potential cardioembolic causes of stroke such as atrial fibrillation, left ventricular aneurysm, or myocardial infarction, but it is insufficient by itself to assess for many other potential sources of cardioembolism.

Transcranial Doppler ultrasonography is very sensitive for detecting patent foramen ovale and other right-to-left shunts that could be sources of cardioembolism. In this test, microbubbles from agitated saline are injected into the venous circulation and are detected in the cerebral arteries after passing through the shunt. It has no utility in identifying the other possibilities discussed above, nor can it discriminate whether these shunts are intra-cardiac or extracardiac.

Case continued

The patient undergoes TTE, which shows normal left ventricular size, wall thickness, and systolic function. His right ventricular function is normal, as are his left and right atrial size. Valvular function is normal, and no right-to-left interatrial shunt is detected with the use of agitated saline contrast.

Figure 3. Left, transesophageal echocardiogram of aortic valve in short-axis view shows papillary fibroelastoma (arrowhead) attached to right coronary cusp. Right, long-axis view.
The patient then undergoes TEE, which reveals a 9- by 8-mm mobile soft-tissue mass attached to the aortic side of the aortic valve at the junction of the right and left coronary cusps (Figure 3). There is trivial aortic insufficiency, and the rest of the aorta appears normal. This lesion is consistent with a valvular papillary fibroelastoma.

 

 

MANAGEMENT

3. Which is the most appropriate way to manage the lesion?

  • Surgical resection
  • Periodic echocardiographic follow-up
  • Anticoagulation and periodic echocardiographic follow-up

Cardiac papillary fibroelastomas are rare benign primary tumors of the heart. The true incidence is unknown because, when small, they can be asymptomatic and easily overlooked on gross examination. In adults, they are the second most common primary cardiac tumors, next to atrial myxoma.26

Figure 4. A, papillary fibroelastomas are composed of fine and coarse branching fingerlike projections that usually arise on valve surfaces. B, the papillary fronds are avascular and composed of dense collagenous cores covered by a single layer of endothelium (hematoxylin and eosin). C, a Movat pentachrome stain shows elastic fibers within the fibrous core (elastin—black; collagen—yellow).
These tumors primarily affect the valves (most often the aortic valve), and consist of a small, highly papillary, avascular tumor covered by a single layer of endothelium, containing variable amounts of fine elastic fibers arranged around a central hyaline stroma (Figure 4).27 Most of the tumors are sessile, while a few are attached to the valve by a short stalk.

The histogenesis is not known, but the mean age at which they are detected is approximately 60 years, and most of the patients are men, likely because most of these tumors are found incidentally during echocardiography, open heart surgery, or autopsy.28

Most patients with cardiac papillary fibroelastomas have no symptoms; however, those who do have symptoms usually experience valve obstruction or embolization of tumor fragments, leading to stroke, myocardial infarction, or sudden death. Further increasing the risk of embolism, thrombus has been reported on the surface of some tumors, supporting the use of anticoagulation in patients who have experienced embolic phenomena.29

A case review of 725 patients with these tumors27 found that tumor mobility and location on the aortic valve were univariate predictors of tumor-related death and of nonfatal embolism. The only independent predictor of tumor-related death or nonfatal embolization was tumor mobility.

Surgical resection of the tumor is curative, and no recurrences have been reported, although the longest follow-up period has been 11 years.

Although no data exist to support the practice, patients with nonmobile or nonaortic valve tumors could be managed with anticoagulation and periodic echocardiographic follow-up until the tumor becomes mobile or symptomatic, but such a conservative strategy would seem inappropriate for our patient. His tumor is both mobile and located on the aortic valve, putting him at risk of death, and he has already experienced an embolic complication. Therefore, his lesion should be surgically resected.

Case continued

The patient receives anticoagulation therapy with subcutaneous enoxaparin (Lovenox) and warfarin (Coumadin). He undergoes successful surgical resection of the tumor without complication and is discharged to home on hospital day 5.

TAKE-HOME POINTS

The potential causes of stroke in patients younger than age 45 differ significantly from those in older patients. Cardiac embolism is the most frequent cause of stroke in young patients and is most often from left atrial or ventricular thrombus or from aortic atheroma.

In young patients, TEE is superior to TTE in identifying a specific source of cardiac embolism, particularly when clues from the history or physical examination are lacking and the preliminary diagnostic workup fails to identify the cause of the stroke.

Our patient’s history, physical examination, MRI, MRA, electrocardiography, and TTE all failed to disclose a probable cause of his stroke. Appropriately, TEE was performed, which confirmed the diagnosis of cardiac papillary fibroelastoma, a rare and benign primary tumor of the heart with the potential for disastrous consequences.

References
  1. Bogousslavsky J, Van Melle G, Regli F. The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke. Stroke 1988; 19:10831092.
  2. Bogousslavsky J, Pierre P. Ischemic stroke in patients under age 45. Neurol Clin 1992; 10:113124.
  3. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001; 344:898906.
  4. Thanvi B, Munshi SK, Dawson SL, Ribinson TG. Carotid and vertebral artery dissection syndromes. Postgrad Med J 2005; 81:383388.
  5. Levine SR. Hypercoagulable states and stroke: a selective review. CNS Spectr 2005; 10:567578.
  6. Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100:310.
  7. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332:912917.
  8. Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001; 32:17931799.
  9. Kaufman MJ, Levin JM, Ross MH, et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 1998; 279:376380.
  10. Kaku DA, Lowenstein DH. Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 1990; 113:821827.
  11. Petitti DB, Sidney S, Quesenberry C, Bernstein A. Stroke and cocaine or amphetamine use. Epidemiology 1998; 9:596600.
  12. Bruno A. Cerebrovascular complications of alcohol and sympathomimetic drug abuse. Curr Neurol Neurosci Rep 2003; 3:4045.
  13. Cardiogenic brain embolism. The second report of the Cerebral Embolism Task Force. Arch Neurol 1989; 46:727743.
  14. Kittner SJ, Stern BJ, Wozniak M, et al. Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Neurology 1998; 50:890894.
  15. Manning WJ. Role of transesophageal echocardiography in the management of thromboembolic stroke. Am J Cardiol 1997; 80 4C:19D28D.
  16. Cheitlin MD, Armstrong WF, Aurigemma GP, et al American College of Cardiology; American Heart Association; American Society of Echocardiography. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation 2003; 108:11461162.
  17. Kizer JR, Devereux RB. Clinical practice. Patent foramen ovale in young adults with unexplained stroke. N Engl J Med 2005; 353:23612372.
  18. Pearson AC. Transthoracic echocardiography versus transesophageal echocardiography in detecting cardiac sources of embolism. Echocardiography 1993; 10:397403.
  19. DeRook FA, Comess KA, Albers GW, Popp RL. Transesophageal echocardiography in the evaluation of stroke. Ann Intern Med 1992; 117:922932.
  20. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17:6672.
  21. Rahmatullah AF, Rahko PS, Stein JH. Transesophageal echocardiography for the evaluation and management of patients with cerebral ischemia. Clin Cardiol 1999; 22:391396.
  22. Come PC, Riley MF, Bivas NK. Roles of echocardiography and arrhythmia monitoring in the evaluation of patients with suspected systemic embolism. Ann Neurol 1983; 13:527531.
  23. Daniel WG, Erbel R, Kasper W, et al. Safety of transesophageal echocardiography. A multicenter survey of 10,419 examinations. Circulation 1991; 83:817821.
  24. Souteyrand G, Motreff P, Lusson JR, et al. Comparison of transthoracic echocardiography using second harmonic imaging, transcranial Doppler and transesophageal echocardiography for the detection of patent foramen ovale in stroke patients. Eur J Echocardiogr 2006; 7:147154.
  25. Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke 2006; 37:859864.
  26. Burke A, Virami R. Tumors of the heart and great vessels. Atlas of Tumor Pathology, 1996, 3rd Series, Fascicle 16. Washington, DC: Armed Forces Institute of Pathology.
  27. Gowda RM, Khan IA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart J 2003; 146:404410.
  28. Edwards FH, Hale D, Cohen A, Thompson L, Pezzella AT, Virmani R. Primary cardiac valve tumors. Ann Thorac Surg 1991; 52:11271131.
  29. Joffe II, Jacobs LE, Owen AN, Ioli A, Kotler MN. Rapid development of a papillary fibroelastoma with associated thrombus: the role of transthoracic and transesophageal echocardiography. Echocardiography 1997; 14:287292.
References
  1. Bogousslavsky J, Van Melle G, Regli F. The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke. Stroke 1988; 19:10831092.
  2. Bogousslavsky J, Pierre P. Ischemic stroke in patients under age 45. Neurol Clin 1992; 10:113124.
  3. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001; 344:898906.
  4. Thanvi B, Munshi SK, Dawson SL, Ribinson TG. Carotid and vertebral artery dissection syndromes. Postgrad Med J 2005; 81:383388.
  5. Levine SR. Hypercoagulable states and stroke: a selective review. CNS Spectr 2005; 10:567578.
  6. Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100:310.
  7. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332:912917.
  8. Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001; 32:17931799.
  9. Kaufman MJ, Levin JM, Ross MH, et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 1998; 279:376380.
  10. Kaku DA, Lowenstein DH. Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 1990; 113:821827.
  11. Petitti DB, Sidney S, Quesenberry C, Bernstein A. Stroke and cocaine or amphetamine use. Epidemiology 1998; 9:596600.
  12. Bruno A. Cerebrovascular complications of alcohol and sympathomimetic drug abuse. Curr Neurol Neurosci Rep 2003; 3:4045.
  13. Cardiogenic brain embolism. The second report of the Cerebral Embolism Task Force. Arch Neurol 1989; 46:727743.
  14. Kittner SJ, Stern BJ, Wozniak M, et al. Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Neurology 1998; 50:890894.
  15. Manning WJ. Role of transesophageal echocardiography in the management of thromboembolic stroke. Am J Cardiol 1997; 80 4C:19D28D.
  16. Cheitlin MD, Armstrong WF, Aurigemma GP, et al American College of Cardiology; American Heart Association; American Society of Echocardiography. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation 2003; 108:11461162.
  17. Kizer JR, Devereux RB. Clinical practice. Patent foramen ovale in young adults with unexplained stroke. N Engl J Med 2005; 353:23612372.
  18. Pearson AC. Transthoracic echocardiography versus transesophageal echocardiography in detecting cardiac sources of embolism. Echocardiography 1993; 10:397403.
  19. DeRook FA, Comess KA, Albers GW, Popp RL. Transesophageal echocardiography in the evaluation of stroke. Ann Intern Med 1992; 117:922932.
  20. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17:6672.
  21. Rahmatullah AF, Rahko PS, Stein JH. Transesophageal echocardiography for the evaluation and management of patients with cerebral ischemia. Clin Cardiol 1999; 22:391396.
  22. Come PC, Riley MF, Bivas NK. Roles of echocardiography and arrhythmia monitoring in the evaluation of patients with suspected systemic embolism. Ann Neurol 1983; 13:527531.
  23. Daniel WG, Erbel R, Kasper W, et al. Safety of transesophageal echocardiography. A multicenter survey of 10,419 examinations. Circulation 1991; 83:817821.
  24. Souteyrand G, Motreff P, Lusson JR, et al. Comparison of transthoracic echocardiography using second harmonic imaging, transcranial Doppler and transesophageal echocardiography for the detection of patent foramen ovale in stroke patients. Eur J Echocardiogr 2006; 7:147154.
  25. Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke 2006; 37:859864.
  26. Burke A, Virami R. Tumors of the heart and great vessels. Atlas of Tumor Pathology, 1996, 3rd Series, Fascicle 16. Washington, DC: Armed Forces Institute of Pathology.
  27. Gowda RM, Khan IA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart J 2003; 146:404410.
  28. Edwards FH, Hale D, Cohen A, Thompson L, Pezzella AT, Virmani R. Primary cardiac valve tumors. Ann Thorac Surg 1991; 52:11271131.
  29. Joffe II, Jacobs LE, Owen AN, Ioli A, Kotler MN. Rapid development of a papillary fibroelastoma with associated thrombus: the role of transthoracic and transesophageal echocardiography. Echocardiography 1997; 14:287292.
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Page Number
145-152
Page Number
145-152
Publications
Publications
Topics
Article Type
Display Headline
A young man with acute weakness of his right arm
Display Headline
A young man with acute weakness of his right arm
Sections
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

Red eye for the internist: When to treat, when to refer

Article Type
Changed
Fri, 06/15/2018 - 06:36
Display Headline
Red eye for the internist: When to treat, when to refer

Many patients present to internists because of redness in the eye. The possible causes range from benign (which generally can be handled by an internist) to vision-threatening (which need prompt or emergency referral to an ophthalmologist).

This article, a primer on red eye for the internist, reviews the conditions that can cause this ocular sign—the ones that internists can comfortably manage and the ones that are best managed by an eye specialist (Table 1).

HISTORY HELPS IDENTIFY THE CAUSE

The internist should ascertain:

  • Whether one or both eyes are affected
  • The duration of symptoms
  • Previous eye and medical problems
  • The type of discharge (watery or purulent), if present
  • Whether the patient has any visual changes, pain, or photosensitivity.

Refer patients to an ophthalmologist for further evaluation if they use contact lenses or if they have had trauma to the eye, vision changes, severe pain, or systemic symptoms such as nausea, vomiting, or severe headache.

BASIC EYE EXAMINATION

Examine:

  • Visual acuity
  • Pupil size and reaction to light
  • The pattern and location of the redness
  • The cornea and anterior segment for gross abnormalities such as corneal opacities, hypopyon (a layer of inflammatory cells in the anterior chamber), and hyphema (hemorrhage in the anterior chamber) (Use a penlight.)
  • The preauricular lymph nodes. Preauricular lymphadenopathy, detected by palpation, suggests but is not specific for viral conjunctivitis.
  • Funduscopy has little value in evaluating a red eye.

Refer immediately anyone who has marked purulent discharge or abnormalities in the cornea or anterior segment.

CONDITIONS A GENERALIST CAN INITIALLY MANAGE

Subconjunctival hemorrhage

Figure 1. Subconjunctival hemorrhage after blunt trauma to the periocular area.
Broken conjunctival blood vessels can bleed into the subconjunctival space (Figure 1). These hemorrhages can occur spontaneously or be due to trauma, the Valsalva maneuver, antiplatelet agents, antithrombotics, or vitamin E in high doses.

Subconjunctival hemorrhages are harmless and do not cause pain or vision changes. No treatment is required, and the blood resorbs within a few weeks. However:

  • Measure the blood pressure—uncontrolled hypertension can present with subconjunctival hemorrhage.1
  • If the patient is on an antithrombotic agent, test the prothrombin and activated partial thromboplastin times.
  • If the patient has recurrent unexplained episodes of subconjunctival hemorrhage, look for a bleeding disorder such as von Willebrand disease, hemophilia, or autoimmune thrombocytopenic purpura.

Blepharitis

Blepharitis, a common condition, is inflammation of the eyelid margins. Anterior blepharitis affects the eyelashes and anterior eyelid margin and is most often caused by a low-grade staphylococcal infection or seborrheic dermatitis. Posterior blepharitis involves the orifices of the slender sebaceous glands of the eyelids (the meibomian glands) and is often associated with acne rosacea.

Symptoms include ocular burning, a sensation that a foreign body is in the eye, and watering. Symptoms are typically worse in the morning and gradually improve throughout the day. Although the onset is sudden in some patients, blepharitis is usually chronic—often lifelong—and starts insidiously.

A sign of anterior blepharitis is crusting around the eyelashes. Patients with concomitant seborrheic dermatitis also have oily skin and flaking from the eyebrows and scalp. Signs of posterior blepharitis are oil inspissation around the meibomian gland openings, telangiectasias of the eyelid margin, and accompanying acne rosacea (skin pustules, telangiectasias, and erythema).

Treat both forms with eyelid hygiene: applying warm compresses to the eyelid margins, followed by gentle massage to remove the debris from the eyelashes and meibomian glands. This is done two to four times daily until acute symptoms resolve, then once daily. Because blepharitis is chronic, eyelid hygiene must be continued indefinitely to prevent acute exacerbations.

Posterior blepharitis that does not respond to hygiene can be also treated with oral tetracycline, which is believed to improve meibomian gland function and alter bacterial colonization.

Some patients also have tear deficiency, which can be addressed with tear replacement therapy (see below).2,3

 

 

Keratoconjunctivitis sicca (dry eye)

Dryness can cause mild eye redness. Patients typically report a foreign body sensation, burning, and paradoxically, watering. Symptoms often worsen as the day progresses and are most prominent at night.

Dryness can be due to:

  • Local disturbances in the tear film such as aqueous deficiency
  • An abnormal eyelid position
  • Systemic autoimmune conditions such as Sjögren syndrome
  • Hormonal changes (eg, in menopause)
  • Excessively dry environments (eg, winter)
  • Medications, including anticholinergics, antihistamines, antidepressants (eg, tricyclics), and antihypertensives (eg, beta-blockers).

Staining the cornea with fluorescein highlights small epithelial defects; rose bengal highlights devitalized cells.

Treat initially with artificial tears (eg, Refresh Tears, GenTeal, Systane, Bion Tears) and ointments (eg, Refresh Liquigel, Lacri-Lube). Dry eye has an inflammatory component; cyclosporine ophthalmic 0.05% (Restasis) may increase tear production and improve symptoms.4

Refer patients with symptoms that do not respond to therapy. An ophthalmologist can place silicone plugs in the canaliculi, a procedure with a 75% success rate for improving dry-eye symptoms.5 Plugs must be carefully fitted: loose ones can spontaneously dislodge, and tight ones can irritate the eye.

Eyelid malposition

Entropion (in-turning of the eyelid) causes eyelashes to rub on the cornea. Ectropion (outward turning of the eyelid) results in tear-film abnormalities and corneal exposure. Both conditions are most commonly caused by aging but may be secondary to scarring or to mechanical, paralytic, or congenital conditions. Definitive treatment involves surgery to restore the normal eyelid position. Several techniques have high success rates.1

Lagophthalmos (inability to fully close the eyes) is caused by orbicularis muscle dysfunction, which may be secondary to Bell palsy, stroke, or neurosurgical procedures that disrupt the facial nerve. The exposed cornea is prone to dryness and irritation. Treatments include artificial tears, lubricating ointments, and surgery—gold weight placement or suturing the eyelid margins (tarsorrhaphy).

Floppy eyelid syndrome refers to a lax upper eyelid that may evert during contact with the pillow during sleep, resulting in irritation and inflammation of the upper palpebral conjunctiva. Signs and symptoms are unilateral eye irritation, burning, and a ropy mucous discharge, which is usually worse in the morning. The upper eyelid is lax and easily everted when pulled toward the eyebrow. Most patients are obese, have obstructive sleep apnea, and sleep on the affected side.

Tell the patient to tape the affected eyelid shut or wear a protective eye shield in bed to prevent rubbing the eye on the pillow. Definitive treatment is surgery to tighten the lax upper eyelid.6

 

 

Conjunctivitis

Conjunctivitis involves hyperemia and edema of the bulbar conjunctiva (the part of the conjunctiva covering the eyeball) along with papillary and follicular changes of the palpebral conjunctiva (the inner layer of the eyelids).

Conjunctivitis can be viral, bacterial, or allergic, or due to wearing contact lenses; the cause can usually be distinguished by the history and physical examination.

Viral conjunctivitis, usually caused by an adenovirus, is more common than bacterial conjunctivitis in adults. The patient typically has had a recent upper respiratory tract infection or was exposed to conjunctivitis.

Figure 2. Viral conjunctivitis with an intensely red eye and a white fibrin membrane in the inferior fornix.
The onset is acute with redness in one eye and excessive watery discharge (Figure 2). The other eye becomes involved within days in about half of cases. Symptoms can include itching, photophobia, watering, and foreign body sensation. Patients often report “matting” and “crusting” of the eyelids in the mornings. Examination reveals follicular conjunctivitis on the lower palpebral conjunctiva and often preauricular lymphadenopathy.

Treat supportively with cool compresses. Symptoms often worsen for a few days, then slowly improve over 1 to 2 weeks.

Viral conjunctivitis is contagious for 2 weeks after the second eye becomes involved, and good hygiene must be maintained to avoid spreading it to coworkers and family members. Those who work with the public, in schools, or in health-care facilities should be given a 2-week leave of absence to avoid spreading the infection to others.

Refer to an ophthalmologist if symptoms do not resolve in 2 weeks, as certain subtypes of adenovirus can cause prolonged symptoms with corneal involvement.7

Figure 3. Bacterial conjunctivitis. Note pus in inferior fornix and along eyelid margins.
Bacterial conjunctivitis can be caused by gram-positive or gram-negative organisms and is differentiated from viral conjunctivitis by thick, purulent discharge rather than excessive watering (Figure 3). Examination reveals papillary conjunctivitis and sometimes preauricular lymphadenopathy.

Treat bacterial conjunctivitis empirically with antibiotic eyedrops (eg, a fluoroquinolone, a polymyxin, or sulfacetamide—several brands available) four times daily for 7 to 10 days, even though most cases are self-limited and do not result in complications. Cultures can be obtained, especially if the patient is in the hospital8 or if the conjunctivitis persists after 1 week of antibiotic therapy.

Refer patients with vision changes or who do not improve after 1 week of treatment.9,10

Figure 4. Hyperacute conjunctivitis caused by Neisseria gonorrhoeae. Note profuse discharge in a very red eye.
Hyperacute bacterial conjunctivitis should be suspected if the onset is abrupt with copious purulent discharge. Most often associated with Neisserria gonorrhoeae infection, it can lead to corneal involvement, including perforation and visual loss (Figure 4).

Treat aggressively with both a topical antibiotic (usually a fluoroquinolone) four times daily and a systemic antibiotic such as ceftriaxone (Rocephin) given as a single 1-g intramuscular injection.11,12 Because one-third of patients with gonorrheal infection also have chlamydial infection, treatment for both diseases is frequently prescribed.

Chlamydial infection, a sexually transmitted disease, can cause chronic follicular conjunctivitis. The genital tract infection may be asymptomatic. Diagnosis is made by swabbing the conjunctiva to culture for Chlamydia trachomatis. Treat systemically with either azithromycin (Zithromax) in a single 1-g oral dose or a 10–14-day course of either doxycycline (Doryx) 100 mg twice daily or erythromycin 250 mg four times daily.13

Allergic conjunctivitis is characterized by bilateral itching that worsens with scratching. Discharge is variable but is usually clear or white and stringy. Many patients have a history of seasonal or perennial allergies.

Remove offending allergens, if possible. Topical mast cell stabilizers and antihistamines relieve symptoms but may exacerbate underlying dry eye symptoms. A combined mast cell stabilizer and antihistamine such as olopatadine (Patanol), ketotifen (Zaditor), or epinastine (Elestat) can be given twice daily.14,15 Artificial tears can treat the associated dryness.

Topical corticosteroids may be used to treat an acute, severe episode but should not be used long-term. In fact, because it is difficult to differentiate between infectious and noninfectious eye conditions, and because treating some infections with corticosteroids by themselves can have grave consequences, we recommend that internists generally refrain from using them.

Oral antihistamines may relieve symptoms but are usually less effective than topical therapy.

Refer if symptoms do not resolve after 2 weeks of topical treatment.

Giant papillary conjunctivitis, most often seen in patients who wear soft contact lenses, presents with bilateral contact lens intolerance, itching, mucous discharge, and giant papillae on the upper palpebral conjunctiva.

Again, promptly refer any patient who wears contact lenses and presents with a red eye, owing to the risk of a vision-threatening corneal infection. The patient should stop wearing contact lenses for about 1 month, after which he or she can be refitted with new soft or gas-permeable lenses and taught better lens hygiene. During an acute episode, topical mast cell stabilizers are helpful for mild irritation, and topical steroids (prednisolone phosphate 1%) are helpful for more severe irritation. Topical steroids should never be used on a long-term basis because of possible adverse effects. Artificial tears can be used for dryness.15

 

 

Corneal abrasion

Figure 5. Corneal abrasion staining brilliantly with fluorescein dye under a cobalt blue filter.
Corneal abrasions (traumatic removal of part of the corneal epithelium) are often caused by fingernails, paper, makeup applicators, metallic foreign bodies, or vegetative matter. Signs and symptoms are pain, photophobia, foreign body sensation, and watering. Depending on the location and severity of the abrasion, visual acuity may be decreased. To see abrasions better, instill fluorescein dye and examine the eye under a light with a cobalt blue filter or under Wood’s lamp illumination (Figure 5).

Treat with topical antibiotics to prevent infection until the corneal epithelium has healed.16 However, most abrasions heal rapidly without sequelae because epithelial cells proliferate and migrate rapidly.

Refer if symptoms persist for longer than 48 hours or if pain suddenly worsens after the healing process has started.

Pingueculae and pterygia

A pinguecula is a small, yellow, benign growth on the nasal and temporal conjunctiva near the limbus. A pterygium is a wing-shaped band of fibrovascular tissue originating on the conjunctiva and extending onto the cornea. Both conditions are idiopathic but are believed to arise from chronic sun exposure.

Pingueculae can become inflamed and can cause eye redness and irritation. Treat conservatively with lubrication and judicious use of topical steroids; if irritation persists, pingueculae can be surgically removed.17

Episcleritis

Episcleritis is inflammation of the superficial vessels of the episclera, the connective tissue layer between the conjunctiva and the sclera. It presents with a sectoral area of redness (although it can be diffuse) and is not typically associated with pain, vision changes, or discharge. The condition tends to be recurrent and unilateral, but it can be bilateral or alternating. The underlying pathophysiology is believed to be autoimmune, although a systemic evaluation is often unrevealing.

Episcleritis is treated with topical corticosteroids or oral nonsteroidal anti-inflammatory drugs (NSAIDs); refer if the disease persists or recurs.

Thyroid-related eye disease

Thyroid-associated ophthalmopathy, an autoimmune process, usually occurs in patients with known thyroid disease, although it may develop before other systemic symptoms. Symptoms can include irritation and double vision. Signs are bulging eyes, eyelid retraction, chemosis (swelling of the conjunctiva around the cornea), conjunctival injection, periorbital edema, and limited ocular motility.

Although most cases can be managed with lubrication, vision loss may occur due to corneal exposure or compressive optic neuropathy. Patients with significant visual changes should be referred immediately to an ophthalmologist.18

CONDITIONS NEEDING REFERRAL WITHIN 48 HOURS

Scleritis

Scleritis is inflammation of the deep vessels within the episclera. The red color appears more pronounced and more purplish than in episcleritis and does not blanch after phenylephrine drops are given. The eye is tender to palpation and may be painful enough to awaken the patient from sleep. Vision is not typically affected unless the cornea, anterior chamber, or posterior segment is involved.

Half of patients who have scleritis have an associated systemic disease, eg, rheumatoid arthritis (most common), other autoimmune diseases (Wegener granulomatosis, relapsing polychondritis, inflammatory bowel disease), or infections such as tuberculosis and syphilis.

Therefore, one should search for an underlying systemic condition with a thorough history, physical examination, chest radiography (for sarcoidosis and tuberculosis), and laboratory testing: antineutrophil cytoplasmic antibody test, fluorescent treponemal antibody absorption test, Lyme antibody test, (if in an endemic area), urinalysis, a complete blood count, and a comprehensive metabolic panel.

However, patients should be promptly referred to an ophthalmologist for diagnosis and management. Treatment can depend on the underlying diagnosis, and is often guided by the status of the scleritis. Mild scleritis can be treated with oral NSAIDs; more severe disease should be treated with oral corticosteroids with or without corticosteroid-sparing agents such as methotrexate, mycophenolate (CellCept), cyclophosphamide (Cytoxan, Neosar),19,20 or tumor necrosis factor-alpha antagonists such as infliximab (Remicade) or etanercept (Enbrel).21

 

 

Anterior uveitis

Uveitis is inflammation of the uvea (the pigmented layer between the sclera and retina that includes the iris, ciliary body, and choroid). Anterior uveitis is most commonly idiopathic but can be caused by trauma, secondary to herpes virus infection, or associated with the HLA-B27 antigen.

Acute anterior uveitis presents with pain, photophobia, and blurred vision. Perilimbal (circumcorneal) injection overlies the inflamed ciliary body. The pupil is often constricted and poorly reactive to light. Chronic anterior uveitis, defined as lasting more than 6 weeks, typically presents with gradual vision loss and floaters, rather than with the acute pain or severe redness of acute disease. Anterior uveitis is diagnosed by finding cells and flare in the anterior chamber using a slit lamp.

Refer patients to an ophthalmologist immediately to help avoid visual consequences.22,23 Treatment begins with topical corticosteroid drops and can also include oral corticosteroids or long-term immunosuppresion with corticosteroid-sparing agents.

Nasolacrimal infections

Canaliculitis is an inflammation of the canaliculus, the conduit bringing tears from the eye to the nasolacrimal duct. It presents with mild, unilateral eye redness and a slight discharge that can be expressed from the punctum. It is most commonly caused by Actinomyces israelii infection, but Candida and Aspergillus species can also be involved.

Refer to an ophthalmologist for treatment, which involves mechanically removing the granular material from the canaliculi, combined with probing and irrigating the nasolacrimal system with penicillin G solution.

Dacryocystitis is inflammation of the lacrimal sac (the dilated upper end of the nasolacrimal duct) and is caused by obstruction of the duct. Staphylococcus and Streptococcus species are usually involved. Symptoms include unilateral pain, swelling, and redness over the lacrimal sac at the medial canthus of the eye. Purulent discharge can be expressed from the punctum.

Treatment consists of oral antibiotics with gram-positive coverage followed by surgery to open a passage for drainage from the lacrimal sac into the nasal cavity (dacryocystorhinostomy) once the infection has resolved.24

CONDITIONS NEEDING IMMEDIATE REFERRAL

Conditions that require immediate referral to an ophthalmologist can be differentiated from more benign conditions by severe pain or vision loss (Table 2).

Acute angle-closure glaucoma

Patients suffering from an episode of acute angle-closure glaucoma report severe eye pain, seeing halos around lights, headache, nausea, and vomiting. Farsighted people and older people are at greater risk, owing to their eye anatomy. The eyeball is firm to palpation, and the pupil is mid-dilated and poorly reactive to light. The cornea may appear hazy.

Acute angle-closure glaucoma is an emergency and requires immediate lowering of intraocular pressure to avoid permanent vision loss.25

Ocular foreign body

A foreign body lodged in or around the eye causes irritation, redness, and pain. Suspect it in any patient with an appropriate history.

Evert the upper eyelid to search for an occult object and remove any loosely adherent exogenous material on the conjunctiva or sclera. Topical broad-spectrum antibiotic ointments or drops can be started.

Immediately refer any patient with a foreign body that does not dislodge easily for removal and management, or if the patient was working near high-speed objects or with metal on metal (raising the possibility of fragments completely penetrating into the eye).26

Keratitis (corneal inflammation)

Keratitis is inflammation at any level of the cornea.

Herpes keratitis presents with unilateral pain, photophobia, and watering. The most common physical finding is a branching ulcer seen with fluorescein staining under Wood’s lamp illumination. Antiviral treatment with an oral medication (acyclovir [Zovirax] 400 mg five times daily) or topical medication (trifluridine 1% [Viroptic] nine times daily) shortens the course of the disease.27,28 Corticosteroid eye-drops should never be given for epithelial herpetic disease without consulting an ophthalmologist.

Bacterial keratitis threatens sight: infection with a virulent bacterium such as Pseudomonas aeruginosa can cause perforation of the cornea within 48 hours. Patients typically report the rapid onset of pain, photophobia, and decreased vision. Common predisposing risk factors include contact lens use and trauma. Examination reveals infiltration, ulceration, and edema of the cornea, and anterior chamber inflammation. Refer immediately to an ophthalmologist for evaluation and management; delaying treatment can have severe visual consequences.29

References
  1. Leibowitz HM. The red eye. N Engl J Med 2000; 343:345351.
  2. Smith RE, Flowers CW. Chronic blepharitis: a review. CLAO J 1995; 21:200207.
  3. McCulley JP, Shine WE. Changing concepts in the diagnosis and management of blepharitis. Cornea 2000; 19:650658.
  4. Smith RE. The tear film complex: pathogenesis and emerging therapies for dry eyes. Cornea 2005; 24:17.
  5. Tai MC, Cosar CB, Cohen EJ, Rapuano CJ, Laibson PR. The clinical efficacy of silicone punctal plug therapy. Cornea 2002; 21:135139.
  6. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthal Plast Reconstr Surg 1997; 13:98114.
  7. Alvarenga L, Marinho S, Mark M.Krachmer JH, Mannis MJ, Holland EJ. Viral conjunctivitis, Cornea. 2005: 1. 2. Philadelphia: Elsevier Mosby;629638.
  8. Tarabishy AB, Hall GS, Procop GW, Jeng BH. Bacterial culture isolates from hospitalized pediatric patients with conjunctivitis. Am J Ophthalmol 2006; 142:678680.
  9. Smith J. Bacterial conjunctivitis. Clin Evid 2004; 12:926932.
  10. Sheikh A, Hurwitz B. Topical antibiotics for acute bacterial conjunctivitis: Cochrane systematic review and meta-analysis update. Br J Gen Pract 2005; 55:962964.
  11. Ullman S, Roussel TJ, Forster RK. Gonococcal keratoconjunctivitis. Surv Ophthalmol 1987; 32:199208.
  12. Deschenes J, Seamone C, Baines M. The ocular manifestations of sexually transmitted diseases. Can J Ophthalmol 1990; 25:177185.
  13. Nakagawa H. Treatment of chlamydial conjunctivitis. Ophthalmologica 1997; 211 suppl 1:2528.
  14. Owen CG, Shah A, Henshaw K, Smeeth L, Sheikh A. Topical treatments for seasonal allergic conjunctivitis: systematic review and meta-analysis of efficacy and effectiveness. Br J Gen Pract 2004; 54:451456.
  15. Stahl JL, Barney NP. Ocular allergic disease. Curr Opin Allergy Clin Immunol 2004; 4:455459.
  16. Galor A, Jeng B, Singh A. Current management of corneal abrasion: an evidence based review. Compr Ophthalmol Update 2005; 5:105111.
  17. Hirst LW. The treatment of pterygium. Surv Ophthalmol 2003; 48:145180.
  18. Mizen TR. Thyroid eye disease. Semin Ophthalmol 2003; 18:243247.
  19. Pavesio CE, Meier FM. Systemic disorders associated with episcleritis and scleritis. Curr Opin Ophthalmol 2001; 12:471478.
  20. Okhravi N, Odufuwa B, McCluskey P, Lightman S. Scleritis. Surv Ophthalmol 2005; 50:351363.
  21. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001; 45:252257.
  22. Chang JH, Wakefield D. Uveitis: a global perspective. Ocul Immunol Inflamm 2002; 10:263279.
  23. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol 2005; 50:364388.
  24. Jordan D.Krachmer JH, Mannis MJ, Holland EJ. Dacryoadenitis, dacryocystitis, and canaliculitis, Cornea. 2005: 1. 2. Philadelphia: Elsevier Mosby;541546.
  25. Saw SM, Gazzard G, Friedman DS. Interventions for angle-closure glaucoma: an evidence-based update. Ophthalmology 2003; 110:18691878.
  26. Khaw PT, Shah P, Elkington AR. Injury to the eye. BMJ 2004; 328:3638.
  27. Suresh PS, Tullo AB. Herpes simplex keratitis. Indian J Ophthalmol 1999; 47:155165.
  28. Tullo A. Pathogenesis and management of herpes simplex virus keratitis. Eye 2003; 17:919922.
  29. Limberg MB. A review of bacterial keratitis and bacterial conjunctivitis. Am J Ophthalmol 1991; 112:2S9S.
Article PDF
Author and Disclosure Information

Anat Galor, MD
Bascom Palmer Eye Institute, University of Miami, Miami, FL

Bennie H. Jeng, MD
Cole Eye Institute, Cleveland Clinic; Assistant Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Bennie H. Jeng, MD, Cole Eye Institute, I-32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]

Dr. Jeng has disclosed that he has received honoraria from Alcon for teaching and speaking.

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Publications
Topics
Page Number
137-144
Sections
Author and Disclosure Information

Anat Galor, MD
Bascom Palmer Eye Institute, University of Miami, Miami, FL

Bennie H. Jeng, MD
Cole Eye Institute, Cleveland Clinic; Assistant Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Bennie H. Jeng, MD, Cole Eye Institute, I-32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]

Dr. Jeng has disclosed that he has received honoraria from Alcon for teaching and speaking.

Author and Disclosure Information

Anat Galor, MD
Bascom Palmer Eye Institute, University of Miami, Miami, FL

Bennie H. Jeng, MD
Cole Eye Institute, Cleveland Clinic; Assistant Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Bennie H. Jeng, MD, Cole Eye Institute, I-32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]

Dr. Jeng has disclosed that he has received honoraria from Alcon for teaching and speaking.

Article PDF
Article PDF

Many patients present to internists because of redness in the eye. The possible causes range from benign (which generally can be handled by an internist) to vision-threatening (which need prompt or emergency referral to an ophthalmologist).

This article, a primer on red eye for the internist, reviews the conditions that can cause this ocular sign—the ones that internists can comfortably manage and the ones that are best managed by an eye specialist (Table 1).

HISTORY HELPS IDENTIFY THE CAUSE

The internist should ascertain:

  • Whether one or both eyes are affected
  • The duration of symptoms
  • Previous eye and medical problems
  • The type of discharge (watery or purulent), if present
  • Whether the patient has any visual changes, pain, or photosensitivity.

Refer patients to an ophthalmologist for further evaluation if they use contact lenses or if they have had trauma to the eye, vision changes, severe pain, or systemic symptoms such as nausea, vomiting, or severe headache.

BASIC EYE EXAMINATION

Examine:

  • Visual acuity
  • Pupil size and reaction to light
  • The pattern and location of the redness
  • The cornea and anterior segment for gross abnormalities such as corneal opacities, hypopyon (a layer of inflammatory cells in the anterior chamber), and hyphema (hemorrhage in the anterior chamber) (Use a penlight.)
  • The preauricular lymph nodes. Preauricular lymphadenopathy, detected by palpation, suggests but is not specific for viral conjunctivitis.
  • Funduscopy has little value in evaluating a red eye.

Refer immediately anyone who has marked purulent discharge or abnormalities in the cornea or anterior segment.

CONDITIONS A GENERALIST CAN INITIALLY MANAGE

Subconjunctival hemorrhage

Figure 1. Subconjunctival hemorrhage after blunt trauma to the periocular area.
Broken conjunctival blood vessels can bleed into the subconjunctival space (Figure 1). These hemorrhages can occur spontaneously or be due to trauma, the Valsalva maneuver, antiplatelet agents, antithrombotics, or vitamin E in high doses.

Subconjunctival hemorrhages are harmless and do not cause pain or vision changes. No treatment is required, and the blood resorbs within a few weeks. However:

  • Measure the blood pressure—uncontrolled hypertension can present with subconjunctival hemorrhage.1
  • If the patient is on an antithrombotic agent, test the prothrombin and activated partial thromboplastin times.
  • If the patient has recurrent unexplained episodes of subconjunctival hemorrhage, look for a bleeding disorder such as von Willebrand disease, hemophilia, or autoimmune thrombocytopenic purpura.

Blepharitis

Blepharitis, a common condition, is inflammation of the eyelid margins. Anterior blepharitis affects the eyelashes and anterior eyelid margin and is most often caused by a low-grade staphylococcal infection or seborrheic dermatitis. Posterior blepharitis involves the orifices of the slender sebaceous glands of the eyelids (the meibomian glands) and is often associated with acne rosacea.

Symptoms include ocular burning, a sensation that a foreign body is in the eye, and watering. Symptoms are typically worse in the morning and gradually improve throughout the day. Although the onset is sudden in some patients, blepharitis is usually chronic—often lifelong—and starts insidiously.

A sign of anterior blepharitis is crusting around the eyelashes. Patients with concomitant seborrheic dermatitis also have oily skin and flaking from the eyebrows and scalp. Signs of posterior blepharitis are oil inspissation around the meibomian gland openings, telangiectasias of the eyelid margin, and accompanying acne rosacea (skin pustules, telangiectasias, and erythema).

Treat both forms with eyelid hygiene: applying warm compresses to the eyelid margins, followed by gentle massage to remove the debris from the eyelashes and meibomian glands. This is done two to four times daily until acute symptoms resolve, then once daily. Because blepharitis is chronic, eyelid hygiene must be continued indefinitely to prevent acute exacerbations.

Posterior blepharitis that does not respond to hygiene can be also treated with oral tetracycline, which is believed to improve meibomian gland function and alter bacterial colonization.

Some patients also have tear deficiency, which can be addressed with tear replacement therapy (see below).2,3

 

 

Keratoconjunctivitis sicca (dry eye)

Dryness can cause mild eye redness. Patients typically report a foreign body sensation, burning, and paradoxically, watering. Symptoms often worsen as the day progresses and are most prominent at night.

Dryness can be due to:

  • Local disturbances in the tear film such as aqueous deficiency
  • An abnormal eyelid position
  • Systemic autoimmune conditions such as Sjögren syndrome
  • Hormonal changes (eg, in menopause)
  • Excessively dry environments (eg, winter)
  • Medications, including anticholinergics, antihistamines, antidepressants (eg, tricyclics), and antihypertensives (eg, beta-blockers).

Staining the cornea with fluorescein highlights small epithelial defects; rose bengal highlights devitalized cells.

Treat initially with artificial tears (eg, Refresh Tears, GenTeal, Systane, Bion Tears) and ointments (eg, Refresh Liquigel, Lacri-Lube). Dry eye has an inflammatory component; cyclosporine ophthalmic 0.05% (Restasis) may increase tear production and improve symptoms.4

Refer patients with symptoms that do not respond to therapy. An ophthalmologist can place silicone plugs in the canaliculi, a procedure with a 75% success rate for improving dry-eye symptoms.5 Plugs must be carefully fitted: loose ones can spontaneously dislodge, and tight ones can irritate the eye.

Eyelid malposition

Entropion (in-turning of the eyelid) causes eyelashes to rub on the cornea. Ectropion (outward turning of the eyelid) results in tear-film abnormalities and corneal exposure. Both conditions are most commonly caused by aging but may be secondary to scarring or to mechanical, paralytic, or congenital conditions. Definitive treatment involves surgery to restore the normal eyelid position. Several techniques have high success rates.1

Lagophthalmos (inability to fully close the eyes) is caused by orbicularis muscle dysfunction, which may be secondary to Bell palsy, stroke, or neurosurgical procedures that disrupt the facial nerve. The exposed cornea is prone to dryness and irritation. Treatments include artificial tears, lubricating ointments, and surgery—gold weight placement or suturing the eyelid margins (tarsorrhaphy).

Floppy eyelid syndrome refers to a lax upper eyelid that may evert during contact with the pillow during sleep, resulting in irritation and inflammation of the upper palpebral conjunctiva. Signs and symptoms are unilateral eye irritation, burning, and a ropy mucous discharge, which is usually worse in the morning. The upper eyelid is lax and easily everted when pulled toward the eyebrow. Most patients are obese, have obstructive sleep apnea, and sleep on the affected side.

Tell the patient to tape the affected eyelid shut or wear a protective eye shield in bed to prevent rubbing the eye on the pillow. Definitive treatment is surgery to tighten the lax upper eyelid.6

 

 

Conjunctivitis

Conjunctivitis involves hyperemia and edema of the bulbar conjunctiva (the part of the conjunctiva covering the eyeball) along with papillary and follicular changes of the palpebral conjunctiva (the inner layer of the eyelids).

Conjunctivitis can be viral, bacterial, or allergic, or due to wearing contact lenses; the cause can usually be distinguished by the history and physical examination.

Viral conjunctivitis, usually caused by an adenovirus, is more common than bacterial conjunctivitis in adults. The patient typically has had a recent upper respiratory tract infection or was exposed to conjunctivitis.

Figure 2. Viral conjunctivitis with an intensely red eye and a white fibrin membrane in the inferior fornix.
The onset is acute with redness in one eye and excessive watery discharge (Figure 2). The other eye becomes involved within days in about half of cases. Symptoms can include itching, photophobia, watering, and foreign body sensation. Patients often report “matting” and “crusting” of the eyelids in the mornings. Examination reveals follicular conjunctivitis on the lower palpebral conjunctiva and often preauricular lymphadenopathy.

Treat supportively with cool compresses. Symptoms often worsen for a few days, then slowly improve over 1 to 2 weeks.

Viral conjunctivitis is contagious for 2 weeks after the second eye becomes involved, and good hygiene must be maintained to avoid spreading it to coworkers and family members. Those who work with the public, in schools, or in health-care facilities should be given a 2-week leave of absence to avoid spreading the infection to others.

Refer to an ophthalmologist if symptoms do not resolve in 2 weeks, as certain subtypes of adenovirus can cause prolonged symptoms with corneal involvement.7

Figure 3. Bacterial conjunctivitis. Note pus in inferior fornix and along eyelid margins.
Bacterial conjunctivitis can be caused by gram-positive or gram-negative organisms and is differentiated from viral conjunctivitis by thick, purulent discharge rather than excessive watering (Figure 3). Examination reveals papillary conjunctivitis and sometimes preauricular lymphadenopathy.

Treat bacterial conjunctivitis empirically with antibiotic eyedrops (eg, a fluoroquinolone, a polymyxin, or sulfacetamide—several brands available) four times daily for 7 to 10 days, even though most cases are self-limited and do not result in complications. Cultures can be obtained, especially if the patient is in the hospital8 or if the conjunctivitis persists after 1 week of antibiotic therapy.

Refer patients with vision changes or who do not improve after 1 week of treatment.9,10

Figure 4. Hyperacute conjunctivitis caused by Neisseria gonorrhoeae. Note profuse discharge in a very red eye.
Hyperacute bacterial conjunctivitis should be suspected if the onset is abrupt with copious purulent discharge. Most often associated with Neisserria gonorrhoeae infection, it can lead to corneal involvement, including perforation and visual loss (Figure 4).

Treat aggressively with both a topical antibiotic (usually a fluoroquinolone) four times daily and a systemic antibiotic such as ceftriaxone (Rocephin) given as a single 1-g intramuscular injection.11,12 Because one-third of patients with gonorrheal infection also have chlamydial infection, treatment for both diseases is frequently prescribed.

Chlamydial infection, a sexually transmitted disease, can cause chronic follicular conjunctivitis. The genital tract infection may be asymptomatic. Diagnosis is made by swabbing the conjunctiva to culture for Chlamydia trachomatis. Treat systemically with either azithromycin (Zithromax) in a single 1-g oral dose or a 10–14-day course of either doxycycline (Doryx) 100 mg twice daily or erythromycin 250 mg four times daily.13

Allergic conjunctivitis is characterized by bilateral itching that worsens with scratching. Discharge is variable but is usually clear or white and stringy. Many patients have a history of seasonal or perennial allergies.

Remove offending allergens, if possible. Topical mast cell stabilizers and antihistamines relieve symptoms but may exacerbate underlying dry eye symptoms. A combined mast cell stabilizer and antihistamine such as olopatadine (Patanol), ketotifen (Zaditor), or epinastine (Elestat) can be given twice daily.14,15 Artificial tears can treat the associated dryness.

Topical corticosteroids may be used to treat an acute, severe episode but should not be used long-term. In fact, because it is difficult to differentiate between infectious and noninfectious eye conditions, and because treating some infections with corticosteroids by themselves can have grave consequences, we recommend that internists generally refrain from using them.

Oral antihistamines may relieve symptoms but are usually less effective than topical therapy.

Refer if symptoms do not resolve after 2 weeks of topical treatment.

Giant papillary conjunctivitis, most often seen in patients who wear soft contact lenses, presents with bilateral contact lens intolerance, itching, mucous discharge, and giant papillae on the upper palpebral conjunctiva.

Again, promptly refer any patient who wears contact lenses and presents with a red eye, owing to the risk of a vision-threatening corneal infection. The patient should stop wearing contact lenses for about 1 month, after which he or she can be refitted with new soft or gas-permeable lenses and taught better lens hygiene. During an acute episode, topical mast cell stabilizers are helpful for mild irritation, and topical steroids (prednisolone phosphate 1%) are helpful for more severe irritation. Topical steroids should never be used on a long-term basis because of possible adverse effects. Artificial tears can be used for dryness.15

 

 

Corneal abrasion

Figure 5. Corneal abrasion staining brilliantly with fluorescein dye under a cobalt blue filter.
Corneal abrasions (traumatic removal of part of the corneal epithelium) are often caused by fingernails, paper, makeup applicators, metallic foreign bodies, or vegetative matter. Signs and symptoms are pain, photophobia, foreign body sensation, and watering. Depending on the location and severity of the abrasion, visual acuity may be decreased. To see abrasions better, instill fluorescein dye and examine the eye under a light with a cobalt blue filter or under Wood’s lamp illumination (Figure 5).

Treat with topical antibiotics to prevent infection until the corneal epithelium has healed.16 However, most abrasions heal rapidly without sequelae because epithelial cells proliferate and migrate rapidly.

Refer if symptoms persist for longer than 48 hours or if pain suddenly worsens after the healing process has started.

Pingueculae and pterygia

A pinguecula is a small, yellow, benign growth on the nasal and temporal conjunctiva near the limbus. A pterygium is a wing-shaped band of fibrovascular tissue originating on the conjunctiva and extending onto the cornea. Both conditions are idiopathic but are believed to arise from chronic sun exposure.

Pingueculae can become inflamed and can cause eye redness and irritation. Treat conservatively with lubrication and judicious use of topical steroids; if irritation persists, pingueculae can be surgically removed.17

Episcleritis

Episcleritis is inflammation of the superficial vessels of the episclera, the connective tissue layer between the conjunctiva and the sclera. It presents with a sectoral area of redness (although it can be diffuse) and is not typically associated with pain, vision changes, or discharge. The condition tends to be recurrent and unilateral, but it can be bilateral or alternating. The underlying pathophysiology is believed to be autoimmune, although a systemic evaluation is often unrevealing.

Episcleritis is treated with topical corticosteroids or oral nonsteroidal anti-inflammatory drugs (NSAIDs); refer if the disease persists or recurs.

Thyroid-related eye disease

Thyroid-associated ophthalmopathy, an autoimmune process, usually occurs in patients with known thyroid disease, although it may develop before other systemic symptoms. Symptoms can include irritation and double vision. Signs are bulging eyes, eyelid retraction, chemosis (swelling of the conjunctiva around the cornea), conjunctival injection, periorbital edema, and limited ocular motility.

Although most cases can be managed with lubrication, vision loss may occur due to corneal exposure or compressive optic neuropathy. Patients with significant visual changes should be referred immediately to an ophthalmologist.18

CONDITIONS NEEDING REFERRAL WITHIN 48 HOURS

Scleritis

Scleritis is inflammation of the deep vessels within the episclera. The red color appears more pronounced and more purplish than in episcleritis and does not blanch after phenylephrine drops are given. The eye is tender to palpation and may be painful enough to awaken the patient from sleep. Vision is not typically affected unless the cornea, anterior chamber, or posterior segment is involved.

Half of patients who have scleritis have an associated systemic disease, eg, rheumatoid arthritis (most common), other autoimmune diseases (Wegener granulomatosis, relapsing polychondritis, inflammatory bowel disease), or infections such as tuberculosis and syphilis.

Therefore, one should search for an underlying systemic condition with a thorough history, physical examination, chest radiography (for sarcoidosis and tuberculosis), and laboratory testing: antineutrophil cytoplasmic antibody test, fluorescent treponemal antibody absorption test, Lyme antibody test, (if in an endemic area), urinalysis, a complete blood count, and a comprehensive metabolic panel.

However, patients should be promptly referred to an ophthalmologist for diagnosis and management. Treatment can depend on the underlying diagnosis, and is often guided by the status of the scleritis. Mild scleritis can be treated with oral NSAIDs; more severe disease should be treated with oral corticosteroids with or without corticosteroid-sparing agents such as methotrexate, mycophenolate (CellCept), cyclophosphamide (Cytoxan, Neosar),19,20 or tumor necrosis factor-alpha antagonists such as infliximab (Remicade) or etanercept (Enbrel).21

 

 

Anterior uveitis

Uveitis is inflammation of the uvea (the pigmented layer between the sclera and retina that includes the iris, ciliary body, and choroid). Anterior uveitis is most commonly idiopathic but can be caused by trauma, secondary to herpes virus infection, or associated with the HLA-B27 antigen.

Acute anterior uveitis presents with pain, photophobia, and blurred vision. Perilimbal (circumcorneal) injection overlies the inflamed ciliary body. The pupil is often constricted and poorly reactive to light. Chronic anterior uveitis, defined as lasting more than 6 weeks, typically presents with gradual vision loss and floaters, rather than with the acute pain or severe redness of acute disease. Anterior uveitis is diagnosed by finding cells and flare in the anterior chamber using a slit lamp.

Refer patients to an ophthalmologist immediately to help avoid visual consequences.22,23 Treatment begins with topical corticosteroid drops and can also include oral corticosteroids or long-term immunosuppresion with corticosteroid-sparing agents.

Nasolacrimal infections

Canaliculitis is an inflammation of the canaliculus, the conduit bringing tears from the eye to the nasolacrimal duct. It presents with mild, unilateral eye redness and a slight discharge that can be expressed from the punctum. It is most commonly caused by Actinomyces israelii infection, but Candida and Aspergillus species can also be involved.

Refer to an ophthalmologist for treatment, which involves mechanically removing the granular material from the canaliculi, combined with probing and irrigating the nasolacrimal system with penicillin G solution.

Dacryocystitis is inflammation of the lacrimal sac (the dilated upper end of the nasolacrimal duct) and is caused by obstruction of the duct. Staphylococcus and Streptococcus species are usually involved. Symptoms include unilateral pain, swelling, and redness over the lacrimal sac at the medial canthus of the eye. Purulent discharge can be expressed from the punctum.

Treatment consists of oral antibiotics with gram-positive coverage followed by surgery to open a passage for drainage from the lacrimal sac into the nasal cavity (dacryocystorhinostomy) once the infection has resolved.24

CONDITIONS NEEDING IMMEDIATE REFERRAL

Conditions that require immediate referral to an ophthalmologist can be differentiated from more benign conditions by severe pain or vision loss (Table 2).

Acute angle-closure glaucoma

Patients suffering from an episode of acute angle-closure glaucoma report severe eye pain, seeing halos around lights, headache, nausea, and vomiting. Farsighted people and older people are at greater risk, owing to their eye anatomy. The eyeball is firm to palpation, and the pupil is mid-dilated and poorly reactive to light. The cornea may appear hazy.

Acute angle-closure glaucoma is an emergency and requires immediate lowering of intraocular pressure to avoid permanent vision loss.25

Ocular foreign body

A foreign body lodged in or around the eye causes irritation, redness, and pain. Suspect it in any patient with an appropriate history.

Evert the upper eyelid to search for an occult object and remove any loosely adherent exogenous material on the conjunctiva or sclera. Topical broad-spectrum antibiotic ointments or drops can be started.

Immediately refer any patient with a foreign body that does not dislodge easily for removal and management, or if the patient was working near high-speed objects or with metal on metal (raising the possibility of fragments completely penetrating into the eye).26

Keratitis (corneal inflammation)

Keratitis is inflammation at any level of the cornea.

Herpes keratitis presents with unilateral pain, photophobia, and watering. The most common physical finding is a branching ulcer seen with fluorescein staining under Wood’s lamp illumination. Antiviral treatment with an oral medication (acyclovir [Zovirax] 400 mg five times daily) or topical medication (trifluridine 1% [Viroptic] nine times daily) shortens the course of the disease.27,28 Corticosteroid eye-drops should never be given for epithelial herpetic disease without consulting an ophthalmologist.

Bacterial keratitis threatens sight: infection with a virulent bacterium such as Pseudomonas aeruginosa can cause perforation of the cornea within 48 hours. Patients typically report the rapid onset of pain, photophobia, and decreased vision. Common predisposing risk factors include contact lens use and trauma. Examination reveals infiltration, ulceration, and edema of the cornea, and anterior chamber inflammation. Refer immediately to an ophthalmologist for evaluation and management; delaying treatment can have severe visual consequences.29

Many patients present to internists because of redness in the eye. The possible causes range from benign (which generally can be handled by an internist) to vision-threatening (which need prompt or emergency referral to an ophthalmologist).

This article, a primer on red eye for the internist, reviews the conditions that can cause this ocular sign—the ones that internists can comfortably manage and the ones that are best managed by an eye specialist (Table 1).

HISTORY HELPS IDENTIFY THE CAUSE

The internist should ascertain:

  • Whether one or both eyes are affected
  • The duration of symptoms
  • Previous eye and medical problems
  • The type of discharge (watery or purulent), if present
  • Whether the patient has any visual changes, pain, or photosensitivity.

Refer patients to an ophthalmologist for further evaluation if they use contact lenses or if they have had trauma to the eye, vision changes, severe pain, or systemic symptoms such as nausea, vomiting, or severe headache.

BASIC EYE EXAMINATION

Examine:

  • Visual acuity
  • Pupil size and reaction to light
  • The pattern and location of the redness
  • The cornea and anterior segment for gross abnormalities such as corneal opacities, hypopyon (a layer of inflammatory cells in the anterior chamber), and hyphema (hemorrhage in the anterior chamber) (Use a penlight.)
  • The preauricular lymph nodes. Preauricular lymphadenopathy, detected by palpation, suggests but is not specific for viral conjunctivitis.
  • Funduscopy has little value in evaluating a red eye.

Refer immediately anyone who has marked purulent discharge or abnormalities in the cornea or anterior segment.

CONDITIONS A GENERALIST CAN INITIALLY MANAGE

Subconjunctival hemorrhage

Figure 1. Subconjunctival hemorrhage after blunt trauma to the periocular area.
Broken conjunctival blood vessels can bleed into the subconjunctival space (Figure 1). These hemorrhages can occur spontaneously or be due to trauma, the Valsalva maneuver, antiplatelet agents, antithrombotics, or vitamin E in high doses.

Subconjunctival hemorrhages are harmless and do not cause pain or vision changes. No treatment is required, and the blood resorbs within a few weeks. However:

  • Measure the blood pressure—uncontrolled hypertension can present with subconjunctival hemorrhage.1
  • If the patient is on an antithrombotic agent, test the prothrombin and activated partial thromboplastin times.
  • If the patient has recurrent unexplained episodes of subconjunctival hemorrhage, look for a bleeding disorder such as von Willebrand disease, hemophilia, or autoimmune thrombocytopenic purpura.

Blepharitis

Blepharitis, a common condition, is inflammation of the eyelid margins. Anterior blepharitis affects the eyelashes and anterior eyelid margin and is most often caused by a low-grade staphylococcal infection or seborrheic dermatitis. Posterior blepharitis involves the orifices of the slender sebaceous glands of the eyelids (the meibomian glands) and is often associated with acne rosacea.

Symptoms include ocular burning, a sensation that a foreign body is in the eye, and watering. Symptoms are typically worse in the morning and gradually improve throughout the day. Although the onset is sudden in some patients, blepharitis is usually chronic—often lifelong—and starts insidiously.

A sign of anterior blepharitis is crusting around the eyelashes. Patients with concomitant seborrheic dermatitis also have oily skin and flaking from the eyebrows and scalp. Signs of posterior blepharitis are oil inspissation around the meibomian gland openings, telangiectasias of the eyelid margin, and accompanying acne rosacea (skin pustules, telangiectasias, and erythema).

Treat both forms with eyelid hygiene: applying warm compresses to the eyelid margins, followed by gentle massage to remove the debris from the eyelashes and meibomian glands. This is done two to four times daily until acute symptoms resolve, then once daily. Because blepharitis is chronic, eyelid hygiene must be continued indefinitely to prevent acute exacerbations.

Posterior blepharitis that does not respond to hygiene can be also treated with oral tetracycline, which is believed to improve meibomian gland function and alter bacterial colonization.

Some patients also have tear deficiency, which can be addressed with tear replacement therapy (see below).2,3

 

 

Keratoconjunctivitis sicca (dry eye)

Dryness can cause mild eye redness. Patients typically report a foreign body sensation, burning, and paradoxically, watering. Symptoms often worsen as the day progresses and are most prominent at night.

Dryness can be due to:

  • Local disturbances in the tear film such as aqueous deficiency
  • An abnormal eyelid position
  • Systemic autoimmune conditions such as Sjögren syndrome
  • Hormonal changes (eg, in menopause)
  • Excessively dry environments (eg, winter)
  • Medications, including anticholinergics, antihistamines, antidepressants (eg, tricyclics), and antihypertensives (eg, beta-blockers).

Staining the cornea with fluorescein highlights small epithelial defects; rose bengal highlights devitalized cells.

Treat initially with artificial tears (eg, Refresh Tears, GenTeal, Systane, Bion Tears) and ointments (eg, Refresh Liquigel, Lacri-Lube). Dry eye has an inflammatory component; cyclosporine ophthalmic 0.05% (Restasis) may increase tear production and improve symptoms.4

Refer patients with symptoms that do not respond to therapy. An ophthalmologist can place silicone plugs in the canaliculi, a procedure with a 75% success rate for improving dry-eye symptoms.5 Plugs must be carefully fitted: loose ones can spontaneously dislodge, and tight ones can irritate the eye.

Eyelid malposition

Entropion (in-turning of the eyelid) causes eyelashes to rub on the cornea. Ectropion (outward turning of the eyelid) results in tear-film abnormalities and corneal exposure. Both conditions are most commonly caused by aging but may be secondary to scarring or to mechanical, paralytic, or congenital conditions. Definitive treatment involves surgery to restore the normal eyelid position. Several techniques have high success rates.1

Lagophthalmos (inability to fully close the eyes) is caused by orbicularis muscle dysfunction, which may be secondary to Bell palsy, stroke, or neurosurgical procedures that disrupt the facial nerve. The exposed cornea is prone to dryness and irritation. Treatments include artificial tears, lubricating ointments, and surgery—gold weight placement or suturing the eyelid margins (tarsorrhaphy).

Floppy eyelid syndrome refers to a lax upper eyelid that may evert during contact with the pillow during sleep, resulting in irritation and inflammation of the upper palpebral conjunctiva. Signs and symptoms are unilateral eye irritation, burning, and a ropy mucous discharge, which is usually worse in the morning. The upper eyelid is lax and easily everted when pulled toward the eyebrow. Most patients are obese, have obstructive sleep apnea, and sleep on the affected side.

Tell the patient to tape the affected eyelid shut or wear a protective eye shield in bed to prevent rubbing the eye on the pillow. Definitive treatment is surgery to tighten the lax upper eyelid.6

 

 

Conjunctivitis

Conjunctivitis involves hyperemia and edema of the bulbar conjunctiva (the part of the conjunctiva covering the eyeball) along with papillary and follicular changes of the palpebral conjunctiva (the inner layer of the eyelids).

Conjunctivitis can be viral, bacterial, or allergic, or due to wearing contact lenses; the cause can usually be distinguished by the history and physical examination.

Viral conjunctivitis, usually caused by an adenovirus, is more common than bacterial conjunctivitis in adults. The patient typically has had a recent upper respiratory tract infection or was exposed to conjunctivitis.

Figure 2. Viral conjunctivitis with an intensely red eye and a white fibrin membrane in the inferior fornix.
The onset is acute with redness in one eye and excessive watery discharge (Figure 2). The other eye becomes involved within days in about half of cases. Symptoms can include itching, photophobia, watering, and foreign body sensation. Patients often report “matting” and “crusting” of the eyelids in the mornings. Examination reveals follicular conjunctivitis on the lower palpebral conjunctiva and often preauricular lymphadenopathy.

Treat supportively with cool compresses. Symptoms often worsen for a few days, then slowly improve over 1 to 2 weeks.

Viral conjunctivitis is contagious for 2 weeks after the second eye becomes involved, and good hygiene must be maintained to avoid spreading it to coworkers and family members. Those who work with the public, in schools, or in health-care facilities should be given a 2-week leave of absence to avoid spreading the infection to others.

Refer to an ophthalmologist if symptoms do not resolve in 2 weeks, as certain subtypes of adenovirus can cause prolonged symptoms with corneal involvement.7

Figure 3. Bacterial conjunctivitis. Note pus in inferior fornix and along eyelid margins.
Bacterial conjunctivitis can be caused by gram-positive or gram-negative organisms and is differentiated from viral conjunctivitis by thick, purulent discharge rather than excessive watering (Figure 3). Examination reveals papillary conjunctivitis and sometimes preauricular lymphadenopathy.

Treat bacterial conjunctivitis empirically with antibiotic eyedrops (eg, a fluoroquinolone, a polymyxin, or sulfacetamide—several brands available) four times daily for 7 to 10 days, even though most cases are self-limited and do not result in complications. Cultures can be obtained, especially if the patient is in the hospital8 or if the conjunctivitis persists after 1 week of antibiotic therapy.

Refer patients with vision changes or who do not improve after 1 week of treatment.9,10

Figure 4. Hyperacute conjunctivitis caused by Neisseria gonorrhoeae. Note profuse discharge in a very red eye.
Hyperacute bacterial conjunctivitis should be suspected if the onset is abrupt with copious purulent discharge. Most often associated with Neisserria gonorrhoeae infection, it can lead to corneal involvement, including perforation and visual loss (Figure 4).

Treat aggressively with both a topical antibiotic (usually a fluoroquinolone) four times daily and a systemic antibiotic such as ceftriaxone (Rocephin) given as a single 1-g intramuscular injection.11,12 Because one-third of patients with gonorrheal infection also have chlamydial infection, treatment for both diseases is frequently prescribed.

Chlamydial infection, a sexually transmitted disease, can cause chronic follicular conjunctivitis. The genital tract infection may be asymptomatic. Diagnosis is made by swabbing the conjunctiva to culture for Chlamydia trachomatis. Treat systemically with either azithromycin (Zithromax) in a single 1-g oral dose or a 10–14-day course of either doxycycline (Doryx) 100 mg twice daily or erythromycin 250 mg four times daily.13

Allergic conjunctivitis is characterized by bilateral itching that worsens with scratching. Discharge is variable but is usually clear or white and stringy. Many patients have a history of seasonal or perennial allergies.

Remove offending allergens, if possible. Topical mast cell stabilizers and antihistamines relieve symptoms but may exacerbate underlying dry eye symptoms. A combined mast cell stabilizer and antihistamine such as olopatadine (Patanol), ketotifen (Zaditor), or epinastine (Elestat) can be given twice daily.14,15 Artificial tears can treat the associated dryness.

Topical corticosteroids may be used to treat an acute, severe episode but should not be used long-term. In fact, because it is difficult to differentiate between infectious and noninfectious eye conditions, and because treating some infections with corticosteroids by themselves can have grave consequences, we recommend that internists generally refrain from using them.

Oral antihistamines may relieve symptoms but are usually less effective than topical therapy.

Refer if symptoms do not resolve after 2 weeks of topical treatment.

Giant papillary conjunctivitis, most often seen in patients who wear soft contact lenses, presents with bilateral contact lens intolerance, itching, mucous discharge, and giant papillae on the upper palpebral conjunctiva.

Again, promptly refer any patient who wears contact lenses and presents with a red eye, owing to the risk of a vision-threatening corneal infection. The patient should stop wearing contact lenses for about 1 month, after which he or she can be refitted with new soft or gas-permeable lenses and taught better lens hygiene. During an acute episode, topical mast cell stabilizers are helpful for mild irritation, and topical steroids (prednisolone phosphate 1%) are helpful for more severe irritation. Topical steroids should never be used on a long-term basis because of possible adverse effects. Artificial tears can be used for dryness.15

 

 

Corneal abrasion

Figure 5. Corneal abrasion staining brilliantly with fluorescein dye under a cobalt blue filter.
Corneal abrasions (traumatic removal of part of the corneal epithelium) are often caused by fingernails, paper, makeup applicators, metallic foreign bodies, or vegetative matter. Signs and symptoms are pain, photophobia, foreign body sensation, and watering. Depending on the location and severity of the abrasion, visual acuity may be decreased. To see abrasions better, instill fluorescein dye and examine the eye under a light with a cobalt blue filter or under Wood’s lamp illumination (Figure 5).

Treat with topical antibiotics to prevent infection until the corneal epithelium has healed.16 However, most abrasions heal rapidly without sequelae because epithelial cells proliferate and migrate rapidly.

Refer if symptoms persist for longer than 48 hours or if pain suddenly worsens after the healing process has started.

Pingueculae and pterygia

A pinguecula is a small, yellow, benign growth on the nasal and temporal conjunctiva near the limbus. A pterygium is a wing-shaped band of fibrovascular tissue originating on the conjunctiva and extending onto the cornea. Both conditions are idiopathic but are believed to arise from chronic sun exposure.

Pingueculae can become inflamed and can cause eye redness and irritation. Treat conservatively with lubrication and judicious use of topical steroids; if irritation persists, pingueculae can be surgically removed.17

Episcleritis

Episcleritis is inflammation of the superficial vessels of the episclera, the connective tissue layer between the conjunctiva and the sclera. It presents with a sectoral area of redness (although it can be diffuse) and is not typically associated with pain, vision changes, or discharge. The condition tends to be recurrent and unilateral, but it can be bilateral or alternating. The underlying pathophysiology is believed to be autoimmune, although a systemic evaluation is often unrevealing.

Episcleritis is treated with topical corticosteroids or oral nonsteroidal anti-inflammatory drugs (NSAIDs); refer if the disease persists or recurs.

Thyroid-related eye disease

Thyroid-associated ophthalmopathy, an autoimmune process, usually occurs in patients with known thyroid disease, although it may develop before other systemic symptoms. Symptoms can include irritation and double vision. Signs are bulging eyes, eyelid retraction, chemosis (swelling of the conjunctiva around the cornea), conjunctival injection, periorbital edema, and limited ocular motility.

Although most cases can be managed with lubrication, vision loss may occur due to corneal exposure or compressive optic neuropathy. Patients with significant visual changes should be referred immediately to an ophthalmologist.18

CONDITIONS NEEDING REFERRAL WITHIN 48 HOURS

Scleritis

Scleritis is inflammation of the deep vessels within the episclera. The red color appears more pronounced and more purplish than in episcleritis and does not blanch after phenylephrine drops are given. The eye is tender to palpation and may be painful enough to awaken the patient from sleep. Vision is not typically affected unless the cornea, anterior chamber, or posterior segment is involved.

Half of patients who have scleritis have an associated systemic disease, eg, rheumatoid arthritis (most common), other autoimmune diseases (Wegener granulomatosis, relapsing polychondritis, inflammatory bowel disease), or infections such as tuberculosis and syphilis.

Therefore, one should search for an underlying systemic condition with a thorough history, physical examination, chest radiography (for sarcoidosis and tuberculosis), and laboratory testing: antineutrophil cytoplasmic antibody test, fluorescent treponemal antibody absorption test, Lyme antibody test, (if in an endemic area), urinalysis, a complete blood count, and a comprehensive metabolic panel.

However, patients should be promptly referred to an ophthalmologist for diagnosis and management. Treatment can depend on the underlying diagnosis, and is often guided by the status of the scleritis. Mild scleritis can be treated with oral NSAIDs; more severe disease should be treated with oral corticosteroids with or without corticosteroid-sparing agents such as methotrexate, mycophenolate (CellCept), cyclophosphamide (Cytoxan, Neosar),19,20 or tumor necrosis factor-alpha antagonists such as infliximab (Remicade) or etanercept (Enbrel).21

 

 

Anterior uveitis

Uveitis is inflammation of the uvea (the pigmented layer between the sclera and retina that includes the iris, ciliary body, and choroid). Anterior uveitis is most commonly idiopathic but can be caused by trauma, secondary to herpes virus infection, or associated with the HLA-B27 antigen.

Acute anterior uveitis presents with pain, photophobia, and blurred vision. Perilimbal (circumcorneal) injection overlies the inflamed ciliary body. The pupil is often constricted and poorly reactive to light. Chronic anterior uveitis, defined as lasting more than 6 weeks, typically presents with gradual vision loss and floaters, rather than with the acute pain or severe redness of acute disease. Anterior uveitis is diagnosed by finding cells and flare in the anterior chamber using a slit lamp.

Refer patients to an ophthalmologist immediately to help avoid visual consequences.22,23 Treatment begins with topical corticosteroid drops and can also include oral corticosteroids or long-term immunosuppresion with corticosteroid-sparing agents.

Nasolacrimal infections

Canaliculitis is an inflammation of the canaliculus, the conduit bringing tears from the eye to the nasolacrimal duct. It presents with mild, unilateral eye redness and a slight discharge that can be expressed from the punctum. It is most commonly caused by Actinomyces israelii infection, but Candida and Aspergillus species can also be involved.

Refer to an ophthalmologist for treatment, which involves mechanically removing the granular material from the canaliculi, combined with probing and irrigating the nasolacrimal system with penicillin G solution.

Dacryocystitis is inflammation of the lacrimal sac (the dilated upper end of the nasolacrimal duct) and is caused by obstruction of the duct. Staphylococcus and Streptococcus species are usually involved. Symptoms include unilateral pain, swelling, and redness over the lacrimal sac at the medial canthus of the eye. Purulent discharge can be expressed from the punctum.

Treatment consists of oral antibiotics with gram-positive coverage followed by surgery to open a passage for drainage from the lacrimal sac into the nasal cavity (dacryocystorhinostomy) once the infection has resolved.24

CONDITIONS NEEDING IMMEDIATE REFERRAL

Conditions that require immediate referral to an ophthalmologist can be differentiated from more benign conditions by severe pain or vision loss (Table 2).

Acute angle-closure glaucoma

Patients suffering from an episode of acute angle-closure glaucoma report severe eye pain, seeing halos around lights, headache, nausea, and vomiting. Farsighted people and older people are at greater risk, owing to their eye anatomy. The eyeball is firm to palpation, and the pupil is mid-dilated and poorly reactive to light. The cornea may appear hazy.

Acute angle-closure glaucoma is an emergency and requires immediate lowering of intraocular pressure to avoid permanent vision loss.25

Ocular foreign body

A foreign body lodged in or around the eye causes irritation, redness, and pain. Suspect it in any patient with an appropriate history.

Evert the upper eyelid to search for an occult object and remove any loosely adherent exogenous material on the conjunctiva or sclera. Topical broad-spectrum antibiotic ointments or drops can be started.

Immediately refer any patient with a foreign body that does not dislodge easily for removal and management, or if the patient was working near high-speed objects or with metal on metal (raising the possibility of fragments completely penetrating into the eye).26

Keratitis (corneal inflammation)

Keratitis is inflammation at any level of the cornea.

Herpes keratitis presents with unilateral pain, photophobia, and watering. The most common physical finding is a branching ulcer seen with fluorescein staining under Wood’s lamp illumination. Antiviral treatment with an oral medication (acyclovir [Zovirax] 400 mg five times daily) or topical medication (trifluridine 1% [Viroptic] nine times daily) shortens the course of the disease.27,28 Corticosteroid eye-drops should never be given for epithelial herpetic disease without consulting an ophthalmologist.

Bacterial keratitis threatens sight: infection with a virulent bacterium such as Pseudomonas aeruginosa can cause perforation of the cornea within 48 hours. Patients typically report the rapid onset of pain, photophobia, and decreased vision. Common predisposing risk factors include contact lens use and trauma. Examination reveals infiltration, ulceration, and edema of the cornea, and anterior chamber inflammation. Refer immediately to an ophthalmologist for evaluation and management; delaying treatment can have severe visual consequences.29

References
  1. Leibowitz HM. The red eye. N Engl J Med 2000; 343:345351.
  2. Smith RE, Flowers CW. Chronic blepharitis: a review. CLAO J 1995; 21:200207.
  3. McCulley JP, Shine WE. Changing concepts in the diagnosis and management of blepharitis. Cornea 2000; 19:650658.
  4. Smith RE. The tear film complex: pathogenesis and emerging therapies for dry eyes. Cornea 2005; 24:17.
  5. Tai MC, Cosar CB, Cohen EJ, Rapuano CJ, Laibson PR. The clinical efficacy of silicone punctal plug therapy. Cornea 2002; 21:135139.
  6. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthal Plast Reconstr Surg 1997; 13:98114.
  7. Alvarenga L, Marinho S, Mark M.Krachmer JH, Mannis MJ, Holland EJ. Viral conjunctivitis, Cornea. 2005: 1. 2. Philadelphia: Elsevier Mosby;629638.
  8. Tarabishy AB, Hall GS, Procop GW, Jeng BH. Bacterial culture isolates from hospitalized pediatric patients with conjunctivitis. Am J Ophthalmol 2006; 142:678680.
  9. Smith J. Bacterial conjunctivitis. Clin Evid 2004; 12:926932.
  10. Sheikh A, Hurwitz B. Topical antibiotics for acute bacterial conjunctivitis: Cochrane systematic review and meta-analysis update. Br J Gen Pract 2005; 55:962964.
  11. Ullman S, Roussel TJ, Forster RK. Gonococcal keratoconjunctivitis. Surv Ophthalmol 1987; 32:199208.
  12. Deschenes J, Seamone C, Baines M. The ocular manifestations of sexually transmitted diseases. Can J Ophthalmol 1990; 25:177185.
  13. Nakagawa H. Treatment of chlamydial conjunctivitis. Ophthalmologica 1997; 211 suppl 1:2528.
  14. Owen CG, Shah A, Henshaw K, Smeeth L, Sheikh A. Topical treatments for seasonal allergic conjunctivitis: systematic review and meta-analysis of efficacy and effectiveness. Br J Gen Pract 2004; 54:451456.
  15. Stahl JL, Barney NP. Ocular allergic disease. Curr Opin Allergy Clin Immunol 2004; 4:455459.
  16. Galor A, Jeng B, Singh A. Current management of corneal abrasion: an evidence based review. Compr Ophthalmol Update 2005; 5:105111.
  17. Hirst LW. The treatment of pterygium. Surv Ophthalmol 2003; 48:145180.
  18. Mizen TR. Thyroid eye disease. Semin Ophthalmol 2003; 18:243247.
  19. Pavesio CE, Meier FM. Systemic disorders associated with episcleritis and scleritis. Curr Opin Ophthalmol 2001; 12:471478.
  20. Okhravi N, Odufuwa B, McCluskey P, Lightman S. Scleritis. Surv Ophthalmol 2005; 50:351363.
  21. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001; 45:252257.
  22. Chang JH, Wakefield D. Uveitis: a global perspective. Ocul Immunol Inflamm 2002; 10:263279.
  23. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol 2005; 50:364388.
  24. Jordan D.Krachmer JH, Mannis MJ, Holland EJ. Dacryoadenitis, dacryocystitis, and canaliculitis, Cornea. 2005: 1. 2. Philadelphia: Elsevier Mosby;541546.
  25. Saw SM, Gazzard G, Friedman DS. Interventions for angle-closure glaucoma: an evidence-based update. Ophthalmology 2003; 110:18691878.
  26. Khaw PT, Shah P, Elkington AR. Injury to the eye. BMJ 2004; 328:3638.
  27. Suresh PS, Tullo AB. Herpes simplex keratitis. Indian J Ophthalmol 1999; 47:155165.
  28. Tullo A. Pathogenesis and management of herpes simplex virus keratitis. Eye 2003; 17:919922.
  29. Limberg MB. A review of bacterial keratitis and bacterial conjunctivitis. Am J Ophthalmol 1991; 112:2S9S.
References
  1. Leibowitz HM. The red eye. N Engl J Med 2000; 343:345351.
  2. Smith RE, Flowers CW. Chronic blepharitis: a review. CLAO J 1995; 21:200207.
  3. McCulley JP, Shine WE. Changing concepts in the diagnosis and management of blepharitis. Cornea 2000; 19:650658.
  4. Smith RE. The tear film complex: pathogenesis and emerging therapies for dry eyes. Cornea 2005; 24:17.
  5. Tai MC, Cosar CB, Cohen EJ, Rapuano CJ, Laibson PR. The clinical efficacy of silicone punctal plug therapy. Cornea 2002; 21:135139.
  6. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthal Plast Reconstr Surg 1997; 13:98114.
  7. Alvarenga L, Marinho S, Mark M.Krachmer JH, Mannis MJ, Holland EJ. Viral conjunctivitis, Cornea. 2005: 1. 2. Philadelphia: Elsevier Mosby;629638.
  8. Tarabishy AB, Hall GS, Procop GW, Jeng BH. Bacterial culture isolates from hospitalized pediatric patients with conjunctivitis. Am J Ophthalmol 2006; 142:678680.
  9. Smith J. Bacterial conjunctivitis. Clin Evid 2004; 12:926932.
  10. Sheikh A, Hurwitz B. Topical antibiotics for acute bacterial conjunctivitis: Cochrane systematic review and meta-analysis update. Br J Gen Pract 2005; 55:962964.
  11. Ullman S, Roussel TJ, Forster RK. Gonococcal keratoconjunctivitis. Surv Ophthalmol 1987; 32:199208.
  12. Deschenes J, Seamone C, Baines M. The ocular manifestations of sexually transmitted diseases. Can J Ophthalmol 1990; 25:177185.
  13. Nakagawa H. Treatment of chlamydial conjunctivitis. Ophthalmologica 1997; 211 suppl 1:2528.
  14. Owen CG, Shah A, Henshaw K, Smeeth L, Sheikh A. Topical treatments for seasonal allergic conjunctivitis: systematic review and meta-analysis of efficacy and effectiveness. Br J Gen Pract 2004; 54:451456.
  15. Stahl JL, Barney NP. Ocular allergic disease. Curr Opin Allergy Clin Immunol 2004; 4:455459.
  16. Galor A, Jeng B, Singh A. Current management of corneal abrasion: an evidence based review. Compr Ophthalmol Update 2005; 5:105111.
  17. Hirst LW. The treatment of pterygium. Surv Ophthalmol 2003; 48:145180.
  18. Mizen TR. Thyroid eye disease. Semin Ophthalmol 2003; 18:243247.
  19. Pavesio CE, Meier FM. Systemic disorders associated with episcleritis and scleritis. Curr Opin Ophthalmol 2001; 12:471478.
  20. Okhravi N, Odufuwa B, McCluskey P, Lightman S. Scleritis. Surv Ophthalmol 2005; 50:351363.
  21. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001; 45:252257.
  22. Chang JH, Wakefield D. Uveitis: a global perspective. Ocul Immunol Inflamm 2002; 10:263279.
  23. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol 2005; 50:364388.
  24. Jordan D.Krachmer JH, Mannis MJ, Holland EJ. Dacryoadenitis, dacryocystitis, and canaliculitis, Cornea. 2005: 1. 2. Philadelphia: Elsevier Mosby;541546.
  25. Saw SM, Gazzard G, Friedman DS. Interventions for angle-closure glaucoma: an evidence-based update. Ophthalmology 2003; 110:18691878.
  26. Khaw PT, Shah P, Elkington AR. Injury to the eye. BMJ 2004; 328:3638.
  27. Suresh PS, Tullo AB. Herpes simplex keratitis. Indian J Ophthalmol 1999; 47:155165.
  28. Tullo A. Pathogenesis and management of herpes simplex virus keratitis. Eye 2003; 17:919922.
  29. Limberg MB. A review of bacterial keratitis and bacterial conjunctivitis. Am J Ophthalmol 1991; 112:2S9S.
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Page Number
137-144
Page Number
137-144
Publications
Publications
Topics
Article Type
Display Headline
Red eye for the internist: When to treat, when to refer
Display Headline
Red eye for the internist: When to treat, when to refer
Sections
Inside the Article

KEY POINTS

  • Blepharitis, conjunctivitis, corneal abrasion, dry eye, and subconjunctival hemorrhage are benign and can usually be managed initially by an internist, although referral is usually indicated if symptoms persist or progress.
  • Patients with corneal bacterial infection, uveitis, scleritis, or acute narrow-angle glaucoma need immediate referral to an ophthalmologist, as do most patients with a red eye who use contact lenses, who have had trauma to the eye, or who have vision changes, severe pain, nausea, vomiting, severe headache, marked purulent discharge, or abnormalities in the cornea or anterior segment.
  • Because it is difficult to distinguish between infectious and noninfectious conditions, and because treating infections with corticosteroids alone can have grave consequences, we recommend that internists generally not use topical corticosteroids to treat eye symptoms.
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

Screen for portopulmonary hypertension, especially in liver transplant candidates

Article Type
Changed
Mon, 04/16/2018 - 16:59
Display Headline
Screen for portopulmonary hypertension, especially in liver transplant candidates

Portopulmonary hypertension poses difficulties for patients with liver disease. The elevated pulmonary artery pressure in this disorder makes liver transplantation more dangerous and in fact may rule out the procedure, although in a selected few patients, medical treatment may enable transplantation to proceed. In any event, portopulmonary hypertension should be looked for in patients with liver disease, especially if liver transplantation is being considered.

In this article we discuss the definition, pathophysiology, clinical features, diagnosis, and management of portopulmonary hypertension.

DEFINED BY HEMODYNAMIC CRITERIA

Portopulmonary hypertension—elevated pulmonary artery pressure due to increased resistance to blood flow in patients with portal hypertension—is one of several pulmonary complications of liver disease. A few others to be aware of are pleural effusions (hepatic hydrothorax), dilatation of the pulmonary vasculature with shunting and hypoxemia (hepatopulmonary syndrome), and elevation in pulmonary pressures due to the high cardiac output usually seen in liver disease (flow phenomenon).

The definition of portopulmonary hypertension has evolved as the various hemodynamic profiles that occur in liver disease and their consequences have been described. Currently, it is defined by the following criteria (obtained by right heart catheterization) in a patient with portal hypertension1:

  • Elevated mean pulmonary artery pressure (> 25 mm Hg at rest, > 30 mm Hg with exercise);
  • Increased pulmonary vascular resistance (> 240 dynes.s.cm−5; pulmonary vascular resistance = [(mean pulmonary artery pressure minus pulmonary artery occlusion pressure) /cardiac output] times 80); and
  • Normal pulmonary artery occlusion pressure (< 15 mm Hg) or an elevated transpulmonary gradient (the mean pulmonary artery pressure minus the pulmonary artery occlusion pressure; abnormal is > 12 mm Hg).

The transpulmonary gradient sometimes helps in further assessing the resistance to blood flow in cases that do not meet the other criteria.2 For example, how should we classify a patient whose mean pulmonary artery pressure is 45 mm Hg but whose pulmonary vascular resistance is only 432 dynes.s.cm−5 and whose pulmonary artery occlusion pressure is slightly high at 18 mm Hg? Although this patient does not meet the hemodynamic criteria for portopulmonary hypertension listed above, intuitively, we should not exclude the diagnosis, as the transpulmonary gradient is high at 27 mm Hg.

FLOW PHENOMENON VS TRUE PORTOPULMONARY HYPERTENSION

The cardiopulmonary hemodynamic profile is different in patients with liver disease than in those without liver disease. Understanding the “normal” hemodynamics in liver disease is paramount in understanding the abnormal hemodynamics that occur in portopulmonary hypertension. In general, patients with liver disease have a high cardiac output at baseline (high flow). They may also have an increased blood volume due to fluid shifts (elevated pulmonary artery occlusion pressure).

Right heart catheterization is necessary to make the diagnosis of portopulmonary hypertension, as pulmonary artery pressures may be increased simply from increases in cardiac output and blood volume without an increase in pulmonary vascular resistance.

Consider, for example, a patient whose mean pulmonary artery pressure is 38 mm Hg, pulmonary artery occlusion pressure 14 mm Hg, and cardiac output 8.8 L/minute. In this case, the pulmonary vascular resistance is 218 dynes.s.cm−5. About 30% to 50% of patients with cirrhosis have this type of hyperdynamic pattern, with high cardiac output, low systemic vascular resistance, and low pulmonary vascular resistance.1,3,4 These patients typically have a much better prognosis than those with portopulmonary hypertension and do well with liver transplantation.

Right heart catheterization is also helpful in assessing whether elevated pulmonary pressures are due to increased volume (increased pulmonary artery occlusion pressure), in which case the patient might benefit from more aggressive diuresis.

In true portopulmonary hypertension, the pulmonary vascular resistance is increased due to obstruction of arterial blood flow. Cardiac output may be elevated initially and then decline as pulmonary hypertension becomes more severe. These hemodynamic patterns have different treatment implications and are important when liver transplantation is being considered.5

HOW COMMON IS PORTOPULMONARY HYPERTENSION?

The incidence and prevalence of portopulmonary hypertension is difficult to assess, as many of the estimates are in patients with severe liver disease undergoing evaluation for liver transplantation. Its prevalence in patients with cirrhosis and refractory ascites has been documented at 16.1%,6 while its prevalence in patients with cirrhosis without refractory ascites has been in the range of 0.25% to 4%.7–9

Overall, about 8% of candidates for liver transplantation have portopulmonary hypertension and are at risk of its complications.10 In view of this figure, screening for it should be performed before proceeding with liver transplantation.

 

 

VASOCONSTRICTION, REMODELING, THROMBOSIS

The pathogenesis of portopulmonary hypertension is not completely understood but likely involves a complex interaction of several mechanisms, including an imbalance of vascular mediators favoring vasoconstriction,11–13 endothelial damage with vascular remodeling due to excessive pulmonary blood flow,14,15 smooth muscle proliferation, and microvascular thrombosis.16,17

The pulmonary endothelium is a complex, dynamic organ capable of influencing a variety of vascular mediators and adapting to changes in pulmonary volume as necessary. Endothelial dysfunction may initiate the vascular changes seen in portopulmonary hypertension.

Endothelin-1 (ET-1) is a potent vasoconstrictor that has been implicated in the pathogenesis of idiopathic pulmonary artery hypertension. ET-1 levels are also increased in cirrhotic patients with refractory ascites.6

Other mediators favoring vasoconstriction include serotonin, angiotensin II, and norepinephrine. Whether these mediators influence the development of portopulmonary hypertension is not clear.

At the same time, production of vasodilatory mediators such as nitric oxide and prostacyclin may be decreased in portopulmonary hypertension, facilitating vascular remodeling and a proliferative vascular response. Prostacyclin is a potent vasodilator normally found in high concentrations in the lungs. Prostacyclin synthase is the precursor enzyme for the production of prostacyclin and is decreased in the lungs of patients with portopulmonary hypertension.18

Another way that portal hypertension may influence lung vascular tone is that endotoxin, cytokines, or both, released from the splanchnic circulation, may bypass the liver and get into the lungs.19 Evidence in support of this is that patients with portosystemic shunting can develop similar pathologic changes in the pulmonary vascular bed that normalize when the shunt is reversed. To date, however, no substance has been definitively identified.

Yet another proposed mechanism is shear stress on the pulmonary endothelium from the hyperdynamic cardiac output, with resultant vascular remodeling; however, other mechanisms must be involved, as not everyone with liver disease develops portopulmonary hypertension (see below).

Krowka MJ, Edwards WD. A spectrum of pulmonary vascular pathology in portopulmonary hypertension. Liver Transplant 2000; 6:241–242. Copyright 2000. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley &amp; Sons, Inc.
Figure 1.
On autopsy, the small pulmonary arteries of patients with portopulmonary hypertension show various combinations of medial hypertrophy, endothelial and smooth muscle cell proliferation, fibrosis, and thrombosis (Figure 1).14,20 The thrombotic lesions are not due to abnormalities in coagulation but rather, possibly, to a combination of endothelial cell injury, platelet aggregation, and impaired blood flow.

These changes are identical to those in idiopathic and familial pulmonary arterial hypertension,21 and indeed, the World Health Organization now classifies portopulmonary hypertension in the same category as these primary forms of pulmonary hypertension rather than in the secondary forms.3

Why doesn’t everyone with liver disease develop portopulmonary hypertension?

The severity of liver disease or degree of portal hypertension does not appear to correlate with the severity of pulmonary hypertension,4 and portopulmonary hypertension does not develop in all patients with portal hypertension. Therefore, it is likely that some patients have a genetic or environmental susceptibility or suffer a “second hit” that triggers dysregulated pulmonary vascular proliferation and contributes to the development of pulmonary hypertension.

Whether genetic mutations play a role in portopulmonary hypertension remains unknown. Such a mutation could be similar to the one identified in the bone morphogenetic protein receptor type 2 gene (BMPR2) in familial pulmonary artery hypertension or the mutation in the activin-like kinase gene (ALK1) seen in pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.22

Current studies are investigating the role that bone-marrow-derived progenitor cells might play in the pathogenesis of portopulmonary hypertension.

CLINICAL FEATURES MAY NOT BE OBVIOUS AT FIRST

In the early stages of portopulmonary hypertension, patients may have no symptoms or only symptoms of liver disease, so it is important to have a high index of suspicion and screen for pulmonary hypertension. As its severity increases, symptoms may include fatigue, dyspnea, abdominal bloating, palpitations, chest pain or pressure, and syncope. The most common presenting symptom is dyspnea on exertion.

Similarly, the findings on physical examination also depend on the severity of pulmonary hypertension. Patients with mild portopulmonary hypertension may have only signs suggesting liver disease, such as spider telangiectases, jaundice, mild lower extremity edema, and ascites. As the severity of portopulmonary hypertension increases, however, findings of right heart pressure-and-volume overload become more obvious. These include peripheral edema, elevation of the jugular venous pressure, a right ventricular lift, a loud pulmonic valve closure, increased split of the second heart sound, a pulsatile liver, or a right-sided third or fourth heart sound.

 

 

SCREEN LIVER TRANSPLANT CANDIDATES

Screening for portopulmonary hypertension should be mandatory in patients undergoing evaluation for liver transplantation. This condition increases the risk of perioperative death, so it is not acceptable to make the diagnosis in the operating room!5

Electrocardiographic abnormalities that may raise the suspicion of portopulmonary hypertension include right atrial or ventricular enlargement and a right bundle branch pattern.

Chest radiographic signs are enlarged central pulmonary arteries and cardiomegaly. These electrocardiographic and radiographic signs tend to reflect advanced pulmonary hypertension.

Pulmonary function testing is not generally helpful, but the diffusing capacity may be decreased.

B-type natriuretic peptide (BNP) measurement may be helpful. BNP is released from the ventricles when the ventricles become dilated (due to pressure or volume overload), as in left or right heart failure. BNP testing is clinically useful in monitoring the severity of disease and the efficacy of treatment in patients with pulmonary hypertension; its role in portopulmonary hypertension requires prospective study.23

Transthoracic Doppler echocardiography is an excellent screening test and should be performed in patients undergoing evaluation for liver transplantation to exclude pulmonary hypertension.1 Findings on echocardiography that suggest portopulmonary hypertension include elevation of right ventricular systolic pressure (RVSP), which is calculated from the peak tricuspid regurgitant velocity (TRV) using the modified Bernoulli equation and an estimate of right atrial pressure (RAP):

RVSP = 4(TRV)2 + RAP.

Right atrial pressure is estimated from the filling characteristics of the inferior vena cava.

Transthoracic Doppler echocardiography has a sensitivity of 97% and a specificity of 77% in diagnosing moderate to severe pulmonary hypertension in patients undergoing evaluation for liver transplantation.24 Using an RVSP cutoff of 40 mm Hg, the sensitivity of Doppler echocardiography is about 80%, specificity 96%, positive predictive value 60%, and negative predictive value 98%.25

At Mayo Clinic, patients with an estimated RVSP greater than 50 mm Hg undergo right heart catheterization (see below). Such patients should also have repeat echocardiography at 1-year intervals to monitor for increasing pulmonary artery pressures5; for those on the waiting list for liver transplantation, the interval should probably be every 6 to 12 months.

RIGHT HEART CATHETERIZATION CONFIRMS THE DIAGNOSIS

The diagnosis of portopulmonary hypertension is confirmed with right heart catheterization to accurately measure pulmonary artery pressures, pulmonary artery occlusion pressure (to exclude volume overload), cardiac output (to exclude high-output pulmonary hypertension), and pulmonary vascular resistance. One study in patients with decompensated cirrhosis and refractory ascites found that a right atrial pressure of 14 mm Hg or greater had a positive predictive value of 83% for pulmonary hypertension.6

Other, potentially treatable causes of pulmonary hypertension must be excluded before diagnosing portopulmonary hypertension. These include thromboembolic disease, interstitial lung disease, connective tissue disease, untreated obstructive sleep apnea, and elevated pulmonary artery pressures due to increased cardiac output.

Vasodilator studies are being done less frequently in patients with portopulmonary hypertension, as they generally cannot tolerate calcium channel blocker therapy. Calcium channel blocker therapy is usually started in patients with idiopathic pulmonary artery hypertension who exhibit a positive vasodilator response. A positive vasodilator response also does not predict survival with or without liver transplantation. Unlike those with idiopathic pulmonary artery hypertension, many patients with portopulmonary hypertension cannot tolerate calcium channel blockers, as some of these drugs can exacerbate edema and portal hypertension.

GENERAL MANAGEMENT

Treatment of mild portopulmonary hypertension (mean pulmonary artery pressure < 35 mm Hg) is debatable. In these cases many patients do not have any symptoms attributable to portopulmonary hypertension, but only symptoms of liver disease, and they have a good functional status. As a group, such patients have not been formally studied to date.

Figure 2. Management algorithm for portopulmonary hypertension.
Patients with moderate to severe portopulmonary hypertension, however, may benefit from treatment aimed at improving symptoms and lowering pulmonary artery pressures and pulmonary vascular resistance (Figure 2).

Anticoagulation is often contraindicated in portopulmonary hypertension because of gastroesophageal varices, thrombocytopenia, or other coagulation abnormalities related to liver disease. If contraindications to anticoagulation do not exist, it should be considered.

Diuretics are a mainstay in the treatment of portopulmonary hypertension, both for the pulmonary hypertension and for the liver disease, especially if ascites or peripheral edema is present.

Oxygen should be given to patients with hypoxemia to keep the saturation greater than 90%.

Beta-blockers: A dilemma

Beta-blockers are used in many patients with liver disease as both primary and secondary prophylaxis of variceal bleeding.

However, one study has shown that in patients with moderate to severe portopulmonary hypertension, beta-blockers are associated with significant worsening of exercise capacity and pulmonary hemodynamic measurements.26 After beta-blockers were withdrawn, the 6-minute walking distance increased in 9 of 10 patients, and cardiac output increased with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance. The increases in cardiac output were related to a 25% increase in heart rate. Long-term follow-up was not reported, and it remains unclear whether rates of gastrointestinal bleeding may increase when beta-blockers are withdrawn.

Beta-blocker therapy in portopulmonary hypertension needs to be carefully considered and if at all possible should be avoided.

 

 

VASODILATOR THERAPY

Several vasodilating or vasomodulating drugs are available. However, much of the information about them comes from studies in patients with idiopathic pulmonary artery hypertension or pulmonary hypertension due to connective tissue disease, and no randomized controlled trials in portopulmonary hypertension have been performed.

Prostanoids

Prostanoids have been used successfully to lower pulmonary pressures in portopulmonary hypertension.

Epoprostenol (Flolan) is a pulmonary and systemic vasodilator as well as an inhibitor of platelet aggregation. It is given as a continuous intravenous infusion via an indwelling central venous catheter and a portable infusion pump. It has a very short half-life, requires mixing, and must be kept cold with ice packs, making it somewhat cumbersome to administer.

This medication has been shown to improve cardiopulmonary hemodynamics and exercise capacity in portopulmonary hypertension, although a survival advantage has not been documented to date.27 In several case series, some patients with portopulmonary hypertension treated with intravenous epoprostenol responded with a reduction in pulmonary pressures and successfully underwent liver transplantation.28–31

Complications of intravenous epoprostenol therapy include central venous catheter thrombosis, infection, and infusion pump failure; a backup pump must be available at all times. Patients with portopulmonary hypertension may also develop progressive splenomegaly and thrombocytopenia that may be due to increased blood flow in the splanchnic circulation.32

Treprostinil (Remodulin) has a longer half-life and does not have to be kept cold. It is given as a 24-hour intravenous or subcutaneous infusion, using an infusion pump that is smaller than that used with epoprostenol.

Although treprostinil is easier for patients to use, larger doses are necessary to achieve the same effect as with epoprostenol. With subcutaneous administration, the biggest drawback is site pain. Prostacyclin-related side effects include flushing, diarrhea, jaw discomfort, and lower extremity pain.

Iloprost (Ventavis) has the advantage of being given by inhalation. It is very short-acting, however, and requires six to nine inhalations per day.

Endothelin receptor blockers

Bosentan (Tracleer) is an oral agent that has been approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary hypertension, including in patients with portopulmonary hypertension who have mild hepatic derangement. This medication is a dual endothelin receptor antagonist, nonselectively blocking the endothelin A and B receptors on the endothelial and vascular smooth muscle cells so that ET-1 cannot bind and cause vasoconstriction.

In approximately 10% of patients, bosentan can cause elevations in aminotransferase, alkaline phosphatase, and bilirubin levels, which therefore must be checked monthly.33 Irreversible hepatic toxicity is uncommon; in most cases, liver function abnormalities return to baseline levels when the medication is stopped. The presumed mechanism is impairment of bile-salt transporters, leading to bile-salt accumulation in the liver.34 Bosentan’s use in patients with liver disease has not been well studied, although several case reports have described its use in patients with portopulmonary hypertension.35–38

Ambrisentan (Letairis) is a selective endothelin receptor-A blocker that has just received FDA approval for the treatment of pulmonary artery hypertension. It has not yet been studied in portopulmonary hypertension. Elevations in liver enzymes and bilirubin may also occur, and monthly monitoring is indicated.

Sildenafil

Another oral agent that might be effective in portopulmonary hypertension is sildenafil (Revatio). A phosphodiesterase-5 inhibitor, it selectively inhibits the cyclic guanosine monophosphatase-specific phosphodiesterase type 5 enzyme that is found in large concentrations in pulmonary artery smooth muscle cells.

In other forms of pulmonary hypertension, sildenafil has been shown to increase cardiac output and decrease pulmonary artery pressures and pulmonary vascular resistance without serious adverse events.39–41

In one reported case, treatment with sildenafil in a patient with portopulmonary hypertension decreased the mean pulmonary artery pressure from 56 mm Hg to 28 to 31 mm Hg, and the patient underwent successful liver transplantation.42 A recent case series of 14 patients with portopulmonary hypertension treated with sildenafil documents some improvement in 6-minute walking distance, suggesting that sildenafil as monotherapy or in combination therapy might be effective in portopulmonary hypertension.43 However, in 3 of these patients, the cardiac index decreased and pulmonary vascular resistance increased.44

We must emphasize that controlled studies in portopulmonary hypertension need to be done to find the optimal therapy.

 

 

LIVER TRANSPLANTATION MAY BENEFIT A FEW PATIENTS

Liver transplantation may be beneficial in highly selected patients with portopulmonary hypertension. However, this condition increases the risk of intraoperative and immediate postoperative complications of liver transplantation, so patients should be carefully evaluated5,45 at a liver transplantation center experienced in its management, including medical treatment with well-defined protocols regarding timing of liver transplantation.

Patients with mean pulmonary artery pressures greater than 50 mm Hg should not undergo liver transplantation. Those with mean pulmonary artery pressure between 35 and 50 mm Hg also have an increased mortality rate and may benefit from prolonged treatment for pulmonary hypertension.5,46

One successful case of living-related liver transplantation in a patient with portopulmonary hypertension has been published.47 (Most other successful transplants were from unrelated cadaver donors.)

Some patients who initially cannot undergo liver transplantation owing to severe pulmonary hypertension may eventually be able to do so if they receive medical therapy that improves their pulmonary hemodynamic profile, decreasing their mean pulmonary artery pressure and pulmonary vascular resistance. This would apply to a small subset of patients with portopulmonary hypertension.

When patients without pulmonary hypertension undergo liver transplantation, right ventricular function is preserved throughout all phases of the surgery.48 Patients with portopulmonary hypertension, however, may develop hemodynamic instability during liver transplantation. The most critical times are the induction of anesthesia, during and after graft reperfusion, and the immediate postoperative period.49,50

During the surgery, patients may require vasodilators if they have worsening pulmonary hypertension, or inotropic medications if they have right ventricular dysfunction and heart failure. In one study,51 eight patients with portopulmonary hypertension diagnosed at anesthesia induction for liver transplantation all required intraoperative vasodilator therapy after graft reperfusion because of marked increases in pulmonary artery pressures and pulmonary vascular resistance.

The increase in blood flow following reperfusion or necessary fluid challenges may exacerbate pulmonary hypertension, resulting in worsening right heart function and backup into the transplanted liver. Infusion of 1 liter of crystalloid over 10 minutes has been shown to increase mean pulmonary artery pressure and pulmonary artery occlusion pressure in liver transplantation candidates without pulmonary hypertension52; this response may be exaggerated in portopulmonary hypertension.

PROGNOSIS VARIES WITH SEVERITY OF DISEASE

The natural history of untreated portopulmonary hypertension varies with the degree of liver disease and the severity of pulmonary hypertension. Transplant-free survival was 85% at 1 year and 38% at 3 years in one study.45 The cardiac index appears to be the most significant prognostic variable.20

In a retrospective study of 78 patients with portopulmonary hypertension treated conservatively (before prostanoids were available) the median survival was 6 months (range 0–84 months) from the time of diagnosis.53 Causes of death included right heart failure, sudden death, gastrointestinal bleeding, and small bowel perforation.

Most of the data on outcomes of drug treatment and liver transplantation in patients with portopulmonary hypertension come from case series and retrospective reviews; prospective trials have been lacking.

If right ventricular function is normal and pulmonary hypertension is mild (mean pulmonary artery pressure < 35 mm Hg), patients tend to do well with liver transplantation.9

Outcomes are worse if pulmonary hypertension is more severe. In a database54 from 10 liver transplant centers from 1996 to 2001, 13 (36%) of 36 patients undergoing liver transplantation died in the hospital, emphasizing the importance of accurately assessing the severity of pulmonary hypertension before attempting liver transplantation.46 The rate was even higher—92%—in those with a mean pulmonary artery pressure greater than 35 mm Hg. The cause of death in severe pulmonary hypertension was failure of the right ventricle.

However, some patients with moderate to severe portopulmonary hypertension have been bridged with medications to lower pulmonary artery pressures and pulmonary vascular resistance so that liver transplantation can be safely done, and some have even been able to discontinue medications because their pulmonary hypertension resolved.29,31,41,42,47

Unlike in hepatopulmonary syndrome, liver transplantation is not the treatment of choice for portopulmonary hypertension, and pulmonary hypertension does not always resolve after liver transplantation. Many patients continue therapy for pulmonary hypertension after liver transplantation. Pulmonary hypertension may resolve, persist, or even develop de novo after liver transplantation.1 If pulmonary hypertension resolves, it does so over a prolonged time—months to years—favoring a vascular remodeling hypothesis as opposed to simply reversing vasoconstriction.

References
  1. Rodriguez-Roisin R, Krowka MJ, Hervé P, Fallon MB; ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 2004; 24:861880.
  2. Krowka MJ, Swanson KL, Frantz RP, et al. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 2006; 44:15021510.
  3. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:5S12S.
  4. Hadengue A, Benhayoun MK, Lebrec D, et al. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991; 100:520528.
  5. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transplant 2000; 6:443450.
  6. Benjaminov FS, Prentice M, Sniderman KW, et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:13551362.
  7. McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983; 127:437441.
  8. Cheng EY, Woehlck H. Pulmonary artery hypertension complicating anesthesia for liver transplantation. Anesthesiology 1992; 77:375378.
  9. Castro M, Krowka MJ, Schroeder DR, et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplantation. Mayo Clin Proc 1996; 71:543551.
  10. Ramsay MA, Simpson BR, Nguyen AT, et al. Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 1997; 3:494500.
  11. Kiely DG, Cargill RI, Struthers AD, et al. Cardiopulmonary effects of endothelin-1 in man. Cardiovasc Res 1997; 33:378386.
  12. Panos RJ, Baker SK. Mediators, cytokines, and growth factors in liver-lung interactions. Clin Chest Med 1996; 17:151169.
  13. Higgenbottam T. Pathophysiology of pulmonary hypertension. Chest 1994; 105:7S12S.
  14. Krowka MJ. Hepatopulmonary syndrome and portopulmonary hypertension: distinction and dilemmas. Hepatology 1997; 25:12821284.
  15. Hongqun L, Lee SS. Cardiopulmonary dysfunction in cirrhosis. Hepatology 2000; 14:600608.
  16. Lebrec D, Brenot F, Simonneau G, et al. Pulmonary arterial hypertension in portal hypertension. Eur Respir J 1998; 11:11531166.
  17. Herve P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in portal hypertension. Eur Respir J 1998; 11:11531166.
  18. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999; 159:19251932.
  19. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363:14611468.
  20. Edwards B, Weir K, Edwards WD, et al. Coexistent pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987; 10:12331238.
  21. Ramsay MAE, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 1997; 3:494500.
  22. Trembath RC. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345:325334.
  23. Leuchte HH, Holzapfel M, Baumgartner RA, et al. Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol 2004; 43:764770.
  24. Kim WR, Krowka MJ, Plevak DJ, et al. Accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in liver transplant candidates. Liver Transplant 2000; 6:453458.
  25. Colle IO, Moreau R, Godinho E, et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology 2003; 37:401409.
  26. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 2006; 130:120126.
  27. Swanson KL, McGoon MD, Krowka MJ. Survival in patients with portopulmonary hypertension [abstract]. Am J Respir Crit Care Med 2003; 167:A693.
  28. Kuo PC, Johnson LB, Plotkin JS, et al. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 1997; 63:604616.
  29. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999; 30:641648.
  30. Kähler CM, Graziadei I, Wiedermann CJ, Kneussl MP, Vogel W. Successful use of continuous intravenous prostacyclin in a patient with severe portopulmonary hypertension. Wien Klin Wochenschr 2000; 112:637640.
  31. Sussman N, Kaza V, Barshes N, et al. Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series. Am J Transplant 2006; 6:21772182.
  32. Findlay JY, Plevak DJ, Krowka MJ, et al. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transplant Surg 1999; 5:381387.
  33. Rubin LJ, Roux S. Bosentan: a dual endothelin receptor antagonist. Expert Opin Invest Drugs 2002; 11:9911002.
  34. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001; 69:223231.
  35. Hinterhuber L, Graziadei IW, Kahler CM, et al. Endothelin-receptor anatgonist treatment of portopulmonary hypertension. Clin Gastroenterol Hepatol 2004; 2:10391042.
  36. Clift PF, Townend JN, Bramhall S, et al. Successful treatment of severe portopulmonary hypertension after liver transplantation by bosentan. Transplantation 2004; 77:17741775.
  37. Halank M, Miehlke S, Hoeffken G, et al. Use of oral endothelin-receptor antagonist bosentan in the treatment of portopulmonary hypertension. Transplantation 2004; 77:17751776.
  38. Kuntzen C, Gulberg V, Gerbes AL. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Gastroenterology 2005; 128:164168.
  39. Watanabe H, Ohashi K, Takeuchi K, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002; 71:398402.
  40. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002; 105:23982403.
  41. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360:895900.
  42. Makisalo H, Koivusalo A, Vakkuri A, et al. Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation. Liver Transplant 2004; 10:945950.
  43. Reichengerger F, Voswinckel R, Steveling E, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J 2006; 28:563567.
  44. Krowka MJ, Swanson KL. How should we treat portopulmonary hypertension? Eur Respir J 2006; 28:466467.
  45. Kawut SM, Taichman DB, Ahya VN, et al. Hemodynamics and survival of patients with portopulmonary hypertension. Liver Transplant 2005; 11:11071111.
  46. Krowka MJ, Mandell MS, Ramsay MA, et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database. Liver Transplant 2004; 10:174182.
  47. Sulica R, Emre S, Poon M. Medical management of portopulmonary hypertension and right heart failure prior to living-related liver transplantation. Congest Heart Fail 2004; 10:192194.
  48. De Wolf AM, Begliomini B, Gasior TA, et al. Right ventricular function during orthotopic liver transplantation. Anesthes Analges 1993; 76:562568.
  49. Csete M. Intraoperative management of liver transplant patients with pulmonary hypertension. Liver Transplant Surg 1997; 3:454455.
  50. Acosta F, Sansano T, Palenciano CG, et al. Portopulmonary hypertension and liver transplantation: hemodynamic consequences at reperfusion. Transplant Proc 2005; 37:38653866.
  51. Taura P, Garcia-Valdecasas JC, Beltran J, et al. Moderate primary pulmonary hypertension in patients undergoing liver transplantation. Anesthes Analges 1996; 83:675680.
  52. Kuo PC, Schroeder RA, Vagelos RH, et al. Volume-mediated pulmonary responses in liver transplant candidates. Clin Transplant 1996; 10:521527.
  53. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991; 17:492498.
  54. Mandell MS, Krowka MJ. Formation of a national database on pulmonary hypertension and hepatopulmonary syndrome in chronic liver disease. Anesthesiology 1997; 87:450451.
Article PDF
Author and Disclosure Information

Karen L. Swanson, DO
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN

Michael J. Krowka, MD
Division of Pulmonary and Critical Care Medicine, and Division of Gastroenterology and Hepatology, Liver Transplant Center, Mayo Clinic, Mayo Clinic, Rochester, MN

Address: Michael J. Krowka, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]

Dr. Krowka has indicated that he has served as a consultant for CoTherix, Inc.

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Publications
Topics
Page Number
121-122, 125-130, 133, 136
Sections
Author and Disclosure Information

Karen L. Swanson, DO
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN

Michael J. Krowka, MD
Division of Pulmonary and Critical Care Medicine, and Division of Gastroenterology and Hepatology, Liver Transplant Center, Mayo Clinic, Mayo Clinic, Rochester, MN

Address: Michael J. Krowka, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]

Dr. Krowka has indicated that he has served as a consultant for CoTherix, Inc.

Author and Disclosure Information

Karen L. Swanson, DO
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN

Michael J. Krowka, MD
Division of Pulmonary and Critical Care Medicine, and Division of Gastroenterology and Hepatology, Liver Transplant Center, Mayo Clinic, Mayo Clinic, Rochester, MN

Address: Michael J. Krowka, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]

Dr. Krowka has indicated that he has served as a consultant for CoTherix, Inc.

Article PDF
Article PDF

Portopulmonary hypertension poses difficulties for patients with liver disease. The elevated pulmonary artery pressure in this disorder makes liver transplantation more dangerous and in fact may rule out the procedure, although in a selected few patients, medical treatment may enable transplantation to proceed. In any event, portopulmonary hypertension should be looked for in patients with liver disease, especially if liver transplantation is being considered.

In this article we discuss the definition, pathophysiology, clinical features, diagnosis, and management of portopulmonary hypertension.

DEFINED BY HEMODYNAMIC CRITERIA

Portopulmonary hypertension—elevated pulmonary artery pressure due to increased resistance to blood flow in patients with portal hypertension—is one of several pulmonary complications of liver disease. A few others to be aware of are pleural effusions (hepatic hydrothorax), dilatation of the pulmonary vasculature with shunting and hypoxemia (hepatopulmonary syndrome), and elevation in pulmonary pressures due to the high cardiac output usually seen in liver disease (flow phenomenon).

The definition of portopulmonary hypertension has evolved as the various hemodynamic profiles that occur in liver disease and their consequences have been described. Currently, it is defined by the following criteria (obtained by right heart catheterization) in a patient with portal hypertension1:

  • Elevated mean pulmonary artery pressure (> 25 mm Hg at rest, > 30 mm Hg with exercise);
  • Increased pulmonary vascular resistance (> 240 dynes.s.cm−5; pulmonary vascular resistance = [(mean pulmonary artery pressure minus pulmonary artery occlusion pressure) /cardiac output] times 80); and
  • Normal pulmonary artery occlusion pressure (< 15 mm Hg) or an elevated transpulmonary gradient (the mean pulmonary artery pressure minus the pulmonary artery occlusion pressure; abnormal is > 12 mm Hg).

The transpulmonary gradient sometimes helps in further assessing the resistance to blood flow in cases that do not meet the other criteria.2 For example, how should we classify a patient whose mean pulmonary artery pressure is 45 mm Hg but whose pulmonary vascular resistance is only 432 dynes.s.cm−5 and whose pulmonary artery occlusion pressure is slightly high at 18 mm Hg? Although this patient does not meet the hemodynamic criteria for portopulmonary hypertension listed above, intuitively, we should not exclude the diagnosis, as the transpulmonary gradient is high at 27 mm Hg.

FLOW PHENOMENON VS TRUE PORTOPULMONARY HYPERTENSION

The cardiopulmonary hemodynamic profile is different in patients with liver disease than in those without liver disease. Understanding the “normal” hemodynamics in liver disease is paramount in understanding the abnormal hemodynamics that occur in portopulmonary hypertension. In general, patients with liver disease have a high cardiac output at baseline (high flow). They may also have an increased blood volume due to fluid shifts (elevated pulmonary artery occlusion pressure).

Right heart catheterization is necessary to make the diagnosis of portopulmonary hypertension, as pulmonary artery pressures may be increased simply from increases in cardiac output and blood volume without an increase in pulmonary vascular resistance.

Consider, for example, a patient whose mean pulmonary artery pressure is 38 mm Hg, pulmonary artery occlusion pressure 14 mm Hg, and cardiac output 8.8 L/minute. In this case, the pulmonary vascular resistance is 218 dynes.s.cm−5. About 30% to 50% of patients with cirrhosis have this type of hyperdynamic pattern, with high cardiac output, low systemic vascular resistance, and low pulmonary vascular resistance.1,3,4 These patients typically have a much better prognosis than those with portopulmonary hypertension and do well with liver transplantation.

Right heart catheterization is also helpful in assessing whether elevated pulmonary pressures are due to increased volume (increased pulmonary artery occlusion pressure), in which case the patient might benefit from more aggressive diuresis.

In true portopulmonary hypertension, the pulmonary vascular resistance is increased due to obstruction of arterial blood flow. Cardiac output may be elevated initially and then decline as pulmonary hypertension becomes more severe. These hemodynamic patterns have different treatment implications and are important when liver transplantation is being considered.5

HOW COMMON IS PORTOPULMONARY HYPERTENSION?

The incidence and prevalence of portopulmonary hypertension is difficult to assess, as many of the estimates are in patients with severe liver disease undergoing evaluation for liver transplantation. Its prevalence in patients with cirrhosis and refractory ascites has been documented at 16.1%,6 while its prevalence in patients with cirrhosis without refractory ascites has been in the range of 0.25% to 4%.7–9

Overall, about 8% of candidates for liver transplantation have portopulmonary hypertension and are at risk of its complications.10 In view of this figure, screening for it should be performed before proceeding with liver transplantation.

 

 

VASOCONSTRICTION, REMODELING, THROMBOSIS

The pathogenesis of portopulmonary hypertension is not completely understood but likely involves a complex interaction of several mechanisms, including an imbalance of vascular mediators favoring vasoconstriction,11–13 endothelial damage with vascular remodeling due to excessive pulmonary blood flow,14,15 smooth muscle proliferation, and microvascular thrombosis.16,17

The pulmonary endothelium is a complex, dynamic organ capable of influencing a variety of vascular mediators and adapting to changes in pulmonary volume as necessary. Endothelial dysfunction may initiate the vascular changes seen in portopulmonary hypertension.

Endothelin-1 (ET-1) is a potent vasoconstrictor that has been implicated in the pathogenesis of idiopathic pulmonary artery hypertension. ET-1 levels are also increased in cirrhotic patients with refractory ascites.6

Other mediators favoring vasoconstriction include serotonin, angiotensin II, and norepinephrine. Whether these mediators influence the development of portopulmonary hypertension is not clear.

At the same time, production of vasodilatory mediators such as nitric oxide and prostacyclin may be decreased in portopulmonary hypertension, facilitating vascular remodeling and a proliferative vascular response. Prostacyclin is a potent vasodilator normally found in high concentrations in the lungs. Prostacyclin synthase is the precursor enzyme for the production of prostacyclin and is decreased in the lungs of patients with portopulmonary hypertension.18

Another way that portal hypertension may influence lung vascular tone is that endotoxin, cytokines, or both, released from the splanchnic circulation, may bypass the liver and get into the lungs.19 Evidence in support of this is that patients with portosystemic shunting can develop similar pathologic changes in the pulmonary vascular bed that normalize when the shunt is reversed. To date, however, no substance has been definitively identified.

Yet another proposed mechanism is shear stress on the pulmonary endothelium from the hyperdynamic cardiac output, with resultant vascular remodeling; however, other mechanisms must be involved, as not everyone with liver disease develops portopulmonary hypertension (see below).

Krowka MJ, Edwards WD. A spectrum of pulmonary vascular pathology in portopulmonary hypertension. Liver Transplant 2000; 6:241–242. Copyright 2000. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley &amp; Sons, Inc.
Figure 1.
On autopsy, the small pulmonary arteries of patients with portopulmonary hypertension show various combinations of medial hypertrophy, endothelial and smooth muscle cell proliferation, fibrosis, and thrombosis (Figure 1).14,20 The thrombotic lesions are not due to abnormalities in coagulation but rather, possibly, to a combination of endothelial cell injury, platelet aggregation, and impaired blood flow.

These changes are identical to those in idiopathic and familial pulmonary arterial hypertension,21 and indeed, the World Health Organization now classifies portopulmonary hypertension in the same category as these primary forms of pulmonary hypertension rather than in the secondary forms.3

Why doesn’t everyone with liver disease develop portopulmonary hypertension?

The severity of liver disease or degree of portal hypertension does not appear to correlate with the severity of pulmonary hypertension,4 and portopulmonary hypertension does not develop in all patients with portal hypertension. Therefore, it is likely that some patients have a genetic or environmental susceptibility or suffer a “second hit” that triggers dysregulated pulmonary vascular proliferation and contributes to the development of pulmonary hypertension.

Whether genetic mutations play a role in portopulmonary hypertension remains unknown. Such a mutation could be similar to the one identified in the bone morphogenetic protein receptor type 2 gene (BMPR2) in familial pulmonary artery hypertension or the mutation in the activin-like kinase gene (ALK1) seen in pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.22

Current studies are investigating the role that bone-marrow-derived progenitor cells might play in the pathogenesis of portopulmonary hypertension.

CLINICAL FEATURES MAY NOT BE OBVIOUS AT FIRST

In the early stages of portopulmonary hypertension, patients may have no symptoms or only symptoms of liver disease, so it is important to have a high index of suspicion and screen for pulmonary hypertension. As its severity increases, symptoms may include fatigue, dyspnea, abdominal bloating, palpitations, chest pain or pressure, and syncope. The most common presenting symptom is dyspnea on exertion.

Similarly, the findings on physical examination also depend on the severity of pulmonary hypertension. Patients with mild portopulmonary hypertension may have only signs suggesting liver disease, such as spider telangiectases, jaundice, mild lower extremity edema, and ascites. As the severity of portopulmonary hypertension increases, however, findings of right heart pressure-and-volume overload become more obvious. These include peripheral edema, elevation of the jugular venous pressure, a right ventricular lift, a loud pulmonic valve closure, increased split of the second heart sound, a pulsatile liver, or a right-sided third or fourth heart sound.

 

 

SCREEN LIVER TRANSPLANT CANDIDATES

Screening for portopulmonary hypertension should be mandatory in patients undergoing evaluation for liver transplantation. This condition increases the risk of perioperative death, so it is not acceptable to make the diagnosis in the operating room!5

Electrocardiographic abnormalities that may raise the suspicion of portopulmonary hypertension include right atrial or ventricular enlargement and a right bundle branch pattern.

Chest radiographic signs are enlarged central pulmonary arteries and cardiomegaly. These electrocardiographic and radiographic signs tend to reflect advanced pulmonary hypertension.

Pulmonary function testing is not generally helpful, but the diffusing capacity may be decreased.

B-type natriuretic peptide (BNP) measurement may be helpful. BNP is released from the ventricles when the ventricles become dilated (due to pressure or volume overload), as in left or right heart failure. BNP testing is clinically useful in monitoring the severity of disease and the efficacy of treatment in patients with pulmonary hypertension; its role in portopulmonary hypertension requires prospective study.23

Transthoracic Doppler echocardiography is an excellent screening test and should be performed in patients undergoing evaluation for liver transplantation to exclude pulmonary hypertension.1 Findings on echocardiography that suggest portopulmonary hypertension include elevation of right ventricular systolic pressure (RVSP), which is calculated from the peak tricuspid regurgitant velocity (TRV) using the modified Bernoulli equation and an estimate of right atrial pressure (RAP):

RVSP = 4(TRV)2 + RAP.

Right atrial pressure is estimated from the filling characteristics of the inferior vena cava.

Transthoracic Doppler echocardiography has a sensitivity of 97% and a specificity of 77% in diagnosing moderate to severe pulmonary hypertension in patients undergoing evaluation for liver transplantation.24 Using an RVSP cutoff of 40 mm Hg, the sensitivity of Doppler echocardiography is about 80%, specificity 96%, positive predictive value 60%, and negative predictive value 98%.25

At Mayo Clinic, patients with an estimated RVSP greater than 50 mm Hg undergo right heart catheterization (see below). Such patients should also have repeat echocardiography at 1-year intervals to monitor for increasing pulmonary artery pressures5; for those on the waiting list for liver transplantation, the interval should probably be every 6 to 12 months.

RIGHT HEART CATHETERIZATION CONFIRMS THE DIAGNOSIS

The diagnosis of portopulmonary hypertension is confirmed with right heart catheterization to accurately measure pulmonary artery pressures, pulmonary artery occlusion pressure (to exclude volume overload), cardiac output (to exclude high-output pulmonary hypertension), and pulmonary vascular resistance. One study in patients with decompensated cirrhosis and refractory ascites found that a right atrial pressure of 14 mm Hg or greater had a positive predictive value of 83% for pulmonary hypertension.6

Other, potentially treatable causes of pulmonary hypertension must be excluded before diagnosing portopulmonary hypertension. These include thromboembolic disease, interstitial lung disease, connective tissue disease, untreated obstructive sleep apnea, and elevated pulmonary artery pressures due to increased cardiac output.

Vasodilator studies are being done less frequently in patients with portopulmonary hypertension, as they generally cannot tolerate calcium channel blocker therapy. Calcium channel blocker therapy is usually started in patients with idiopathic pulmonary artery hypertension who exhibit a positive vasodilator response. A positive vasodilator response also does not predict survival with or without liver transplantation. Unlike those with idiopathic pulmonary artery hypertension, many patients with portopulmonary hypertension cannot tolerate calcium channel blockers, as some of these drugs can exacerbate edema and portal hypertension.

GENERAL MANAGEMENT

Treatment of mild portopulmonary hypertension (mean pulmonary artery pressure < 35 mm Hg) is debatable. In these cases many patients do not have any symptoms attributable to portopulmonary hypertension, but only symptoms of liver disease, and they have a good functional status. As a group, such patients have not been formally studied to date.

Figure 2. Management algorithm for portopulmonary hypertension.
Patients with moderate to severe portopulmonary hypertension, however, may benefit from treatment aimed at improving symptoms and lowering pulmonary artery pressures and pulmonary vascular resistance (Figure 2).

Anticoagulation is often contraindicated in portopulmonary hypertension because of gastroesophageal varices, thrombocytopenia, or other coagulation abnormalities related to liver disease. If contraindications to anticoagulation do not exist, it should be considered.

Diuretics are a mainstay in the treatment of portopulmonary hypertension, both for the pulmonary hypertension and for the liver disease, especially if ascites or peripheral edema is present.

Oxygen should be given to patients with hypoxemia to keep the saturation greater than 90%.

Beta-blockers: A dilemma

Beta-blockers are used in many patients with liver disease as both primary and secondary prophylaxis of variceal bleeding.

However, one study has shown that in patients with moderate to severe portopulmonary hypertension, beta-blockers are associated with significant worsening of exercise capacity and pulmonary hemodynamic measurements.26 After beta-blockers were withdrawn, the 6-minute walking distance increased in 9 of 10 patients, and cardiac output increased with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance. The increases in cardiac output were related to a 25% increase in heart rate. Long-term follow-up was not reported, and it remains unclear whether rates of gastrointestinal bleeding may increase when beta-blockers are withdrawn.

Beta-blocker therapy in portopulmonary hypertension needs to be carefully considered and if at all possible should be avoided.

 

 

VASODILATOR THERAPY

Several vasodilating or vasomodulating drugs are available. However, much of the information about them comes from studies in patients with idiopathic pulmonary artery hypertension or pulmonary hypertension due to connective tissue disease, and no randomized controlled trials in portopulmonary hypertension have been performed.

Prostanoids

Prostanoids have been used successfully to lower pulmonary pressures in portopulmonary hypertension.

Epoprostenol (Flolan) is a pulmonary and systemic vasodilator as well as an inhibitor of platelet aggregation. It is given as a continuous intravenous infusion via an indwelling central venous catheter and a portable infusion pump. It has a very short half-life, requires mixing, and must be kept cold with ice packs, making it somewhat cumbersome to administer.

This medication has been shown to improve cardiopulmonary hemodynamics and exercise capacity in portopulmonary hypertension, although a survival advantage has not been documented to date.27 In several case series, some patients with portopulmonary hypertension treated with intravenous epoprostenol responded with a reduction in pulmonary pressures and successfully underwent liver transplantation.28–31

Complications of intravenous epoprostenol therapy include central venous catheter thrombosis, infection, and infusion pump failure; a backup pump must be available at all times. Patients with portopulmonary hypertension may also develop progressive splenomegaly and thrombocytopenia that may be due to increased blood flow in the splanchnic circulation.32

Treprostinil (Remodulin) has a longer half-life and does not have to be kept cold. It is given as a 24-hour intravenous or subcutaneous infusion, using an infusion pump that is smaller than that used with epoprostenol.

Although treprostinil is easier for patients to use, larger doses are necessary to achieve the same effect as with epoprostenol. With subcutaneous administration, the biggest drawback is site pain. Prostacyclin-related side effects include flushing, diarrhea, jaw discomfort, and lower extremity pain.

Iloprost (Ventavis) has the advantage of being given by inhalation. It is very short-acting, however, and requires six to nine inhalations per day.

Endothelin receptor blockers

Bosentan (Tracleer) is an oral agent that has been approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary hypertension, including in patients with portopulmonary hypertension who have mild hepatic derangement. This medication is a dual endothelin receptor antagonist, nonselectively blocking the endothelin A and B receptors on the endothelial and vascular smooth muscle cells so that ET-1 cannot bind and cause vasoconstriction.

In approximately 10% of patients, bosentan can cause elevations in aminotransferase, alkaline phosphatase, and bilirubin levels, which therefore must be checked monthly.33 Irreversible hepatic toxicity is uncommon; in most cases, liver function abnormalities return to baseline levels when the medication is stopped. The presumed mechanism is impairment of bile-salt transporters, leading to bile-salt accumulation in the liver.34 Bosentan’s use in patients with liver disease has not been well studied, although several case reports have described its use in patients with portopulmonary hypertension.35–38

Ambrisentan (Letairis) is a selective endothelin receptor-A blocker that has just received FDA approval for the treatment of pulmonary artery hypertension. It has not yet been studied in portopulmonary hypertension. Elevations in liver enzymes and bilirubin may also occur, and monthly monitoring is indicated.

Sildenafil

Another oral agent that might be effective in portopulmonary hypertension is sildenafil (Revatio). A phosphodiesterase-5 inhibitor, it selectively inhibits the cyclic guanosine monophosphatase-specific phosphodiesterase type 5 enzyme that is found in large concentrations in pulmonary artery smooth muscle cells.

In other forms of pulmonary hypertension, sildenafil has been shown to increase cardiac output and decrease pulmonary artery pressures and pulmonary vascular resistance without serious adverse events.39–41

In one reported case, treatment with sildenafil in a patient with portopulmonary hypertension decreased the mean pulmonary artery pressure from 56 mm Hg to 28 to 31 mm Hg, and the patient underwent successful liver transplantation.42 A recent case series of 14 patients with portopulmonary hypertension treated with sildenafil documents some improvement in 6-minute walking distance, suggesting that sildenafil as monotherapy or in combination therapy might be effective in portopulmonary hypertension.43 However, in 3 of these patients, the cardiac index decreased and pulmonary vascular resistance increased.44

We must emphasize that controlled studies in portopulmonary hypertension need to be done to find the optimal therapy.

 

 

LIVER TRANSPLANTATION MAY BENEFIT A FEW PATIENTS

Liver transplantation may be beneficial in highly selected patients with portopulmonary hypertension. However, this condition increases the risk of intraoperative and immediate postoperative complications of liver transplantation, so patients should be carefully evaluated5,45 at a liver transplantation center experienced in its management, including medical treatment with well-defined protocols regarding timing of liver transplantation.

Patients with mean pulmonary artery pressures greater than 50 mm Hg should not undergo liver transplantation. Those with mean pulmonary artery pressure between 35 and 50 mm Hg also have an increased mortality rate and may benefit from prolonged treatment for pulmonary hypertension.5,46

One successful case of living-related liver transplantation in a patient with portopulmonary hypertension has been published.47 (Most other successful transplants were from unrelated cadaver donors.)

Some patients who initially cannot undergo liver transplantation owing to severe pulmonary hypertension may eventually be able to do so if they receive medical therapy that improves their pulmonary hemodynamic profile, decreasing their mean pulmonary artery pressure and pulmonary vascular resistance. This would apply to a small subset of patients with portopulmonary hypertension.

When patients without pulmonary hypertension undergo liver transplantation, right ventricular function is preserved throughout all phases of the surgery.48 Patients with portopulmonary hypertension, however, may develop hemodynamic instability during liver transplantation. The most critical times are the induction of anesthesia, during and after graft reperfusion, and the immediate postoperative period.49,50

During the surgery, patients may require vasodilators if they have worsening pulmonary hypertension, or inotropic medications if they have right ventricular dysfunction and heart failure. In one study,51 eight patients with portopulmonary hypertension diagnosed at anesthesia induction for liver transplantation all required intraoperative vasodilator therapy after graft reperfusion because of marked increases in pulmonary artery pressures and pulmonary vascular resistance.

The increase in blood flow following reperfusion or necessary fluid challenges may exacerbate pulmonary hypertension, resulting in worsening right heart function and backup into the transplanted liver. Infusion of 1 liter of crystalloid over 10 minutes has been shown to increase mean pulmonary artery pressure and pulmonary artery occlusion pressure in liver transplantation candidates without pulmonary hypertension52; this response may be exaggerated in portopulmonary hypertension.

PROGNOSIS VARIES WITH SEVERITY OF DISEASE

The natural history of untreated portopulmonary hypertension varies with the degree of liver disease and the severity of pulmonary hypertension. Transplant-free survival was 85% at 1 year and 38% at 3 years in one study.45 The cardiac index appears to be the most significant prognostic variable.20

In a retrospective study of 78 patients with portopulmonary hypertension treated conservatively (before prostanoids were available) the median survival was 6 months (range 0–84 months) from the time of diagnosis.53 Causes of death included right heart failure, sudden death, gastrointestinal bleeding, and small bowel perforation.

Most of the data on outcomes of drug treatment and liver transplantation in patients with portopulmonary hypertension come from case series and retrospective reviews; prospective trials have been lacking.

If right ventricular function is normal and pulmonary hypertension is mild (mean pulmonary artery pressure < 35 mm Hg), patients tend to do well with liver transplantation.9

Outcomes are worse if pulmonary hypertension is more severe. In a database54 from 10 liver transplant centers from 1996 to 2001, 13 (36%) of 36 patients undergoing liver transplantation died in the hospital, emphasizing the importance of accurately assessing the severity of pulmonary hypertension before attempting liver transplantation.46 The rate was even higher—92%—in those with a mean pulmonary artery pressure greater than 35 mm Hg. The cause of death in severe pulmonary hypertension was failure of the right ventricle.

However, some patients with moderate to severe portopulmonary hypertension have been bridged with medications to lower pulmonary artery pressures and pulmonary vascular resistance so that liver transplantation can be safely done, and some have even been able to discontinue medications because their pulmonary hypertension resolved.29,31,41,42,47

Unlike in hepatopulmonary syndrome, liver transplantation is not the treatment of choice for portopulmonary hypertension, and pulmonary hypertension does not always resolve after liver transplantation. Many patients continue therapy for pulmonary hypertension after liver transplantation. Pulmonary hypertension may resolve, persist, or even develop de novo after liver transplantation.1 If pulmonary hypertension resolves, it does so over a prolonged time—months to years—favoring a vascular remodeling hypothesis as opposed to simply reversing vasoconstriction.

Portopulmonary hypertension poses difficulties for patients with liver disease. The elevated pulmonary artery pressure in this disorder makes liver transplantation more dangerous and in fact may rule out the procedure, although in a selected few patients, medical treatment may enable transplantation to proceed. In any event, portopulmonary hypertension should be looked for in patients with liver disease, especially if liver transplantation is being considered.

In this article we discuss the definition, pathophysiology, clinical features, diagnosis, and management of portopulmonary hypertension.

DEFINED BY HEMODYNAMIC CRITERIA

Portopulmonary hypertension—elevated pulmonary artery pressure due to increased resistance to blood flow in patients with portal hypertension—is one of several pulmonary complications of liver disease. A few others to be aware of are pleural effusions (hepatic hydrothorax), dilatation of the pulmonary vasculature with shunting and hypoxemia (hepatopulmonary syndrome), and elevation in pulmonary pressures due to the high cardiac output usually seen in liver disease (flow phenomenon).

The definition of portopulmonary hypertension has evolved as the various hemodynamic profiles that occur in liver disease and their consequences have been described. Currently, it is defined by the following criteria (obtained by right heart catheterization) in a patient with portal hypertension1:

  • Elevated mean pulmonary artery pressure (> 25 mm Hg at rest, > 30 mm Hg with exercise);
  • Increased pulmonary vascular resistance (> 240 dynes.s.cm−5; pulmonary vascular resistance = [(mean pulmonary artery pressure minus pulmonary artery occlusion pressure) /cardiac output] times 80); and
  • Normal pulmonary artery occlusion pressure (< 15 mm Hg) or an elevated transpulmonary gradient (the mean pulmonary artery pressure minus the pulmonary artery occlusion pressure; abnormal is > 12 mm Hg).

The transpulmonary gradient sometimes helps in further assessing the resistance to blood flow in cases that do not meet the other criteria.2 For example, how should we classify a patient whose mean pulmonary artery pressure is 45 mm Hg but whose pulmonary vascular resistance is only 432 dynes.s.cm−5 and whose pulmonary artery occlusion pressure is slightly high at 18 mm Hg? Although this patient does not meet the hemodynamic criteria for portopulmonary hypertension listed above, intuitively, we should not exclude the diagnosis, as the transpulmonary gradient is high at 27 mm Hg.

FLOW PHENOMENON VS TRUE PORTOPULMONARY HYPERTENSION

The cardiopulmonary hemodynamic profile is different in patients with liver disease than in those without liver disease. Understanding the “normal” hemodynamics in liver disease is paramount in understanding the abnormal hemodynamics that occur in portopulmonary hypertension. In general, patients with liver disease have a high cardiac output at baseline (high flow). They may also have an increased blood volume due to fluid shifts (elevated pulmonary artery occlusion pressure).

Right heart catheterization is necessary to make the diagnosis of portopulmonary hypertension, as pulmonary artery pressures may be increased simply from increases in cardiac output and blood volume without an increase in pulmonary vascular resistance.

Consider, for example, a patient whose mean pulmonary artery pressure is 38 mm Hg, pulmonary artery occlusion pressure 14 mm Hg, and cardiac output 8.8 L/minute. In this case, the pulmonary vascular resistance is 218 dynes.s.cm−5. About 30% to 50% of patients with cirrhosis have this type of hyperdynamic pattern, with high cardiac output, low systemic vascular resistance, and low pulmonary vascular resistance.1,3,4 These patients typically have a much better prognosis than those with portopulmonary hypertension and do well with liver transplantation.

Right heart catheterization is also helpful in assessing whether elevated pulmonary pressures are due to increased volume (increased pulmonary artery occlusion pressure), in which case the patient might benefit from more aggressive diuresis.

In true portopulmonary hypertension, the pulmonary vascular resistance is increased due to obstruction of arterial blood flow. Cardiac output may be elevated initially and then decline as pulmonary hypertension becomes more severe. These hemodynamic patterns have different treatment implications and are important when liver transplantation is being considered.5

HOW COMMON IS PORTOPULMONARY HYPERTENSION?

The incidence and prevalence of portopulmonary hypertension is difficult to assess, as many of the estimates are in patients with severe liver disease undergoing evaluation for liver transplantation. Its prevalence in patients with cirrhosis and refractory ascites has been documented at 16.1%,6 while its prevalence in patients with cirrhosis without refractory ascites has been in the range of 0.25% to 4%.7–9

Overall, about 8% of candidates for liver transplantation have portopulmonary hypertension and are at risk of its complications.10 In view of this figure, screening for it should be performed before proceeding with liver transplantation.

 

 

VASOCONSTRICTION, REMODELING, THROMBOSIS

The pathogenesis of portopulmonary hypertension is not completely understood but likely involves a complex interaction of several mechanisms, including an imbalance of vascular mediators favoring vasoconstriction,11–13 endothelial damage with vascular remodeling due to excessive pulmonary blood flow,14,15 smooth muscle proliferation, and microvascular thrombosis.16,17

The pulmonary endothelium is a complex, dynamic organ capable of influencing a variety of vascular mediators and adapting to changes in pulmonary volume as necessary. Endothelial dysfunction may initiate the vascular changes seen in portopulmonary hypertension.

Endothelin-1 (ET-1) is a potent vasoconstrictor that has been implicated in the pathogenesis of idiopathic pulmonary artery hypertension. ET-1 levels are also increased in cirrhotic patients with refractory ascites.6

Other mediators favoring vasoconstriction include serotonin, angiotensin II, and norepinephrine. Whether these mediators influence the development of portopulmonary hypertension is not clear.

At the same time, production of vasodilatory mediators such as nitric oxide and prostacyclin may be decreased in portopulmonary hypertension, facilitating vascular remodeling and a proliferative vascular response. Prostacyclin is a potent vasodilator normally found in high concentrations in the lungs. Prostacyclin synthase is the precursor enzyme for the production of prostacyclin and is decreased in the lungs of patients with portopulmonary hypertension.18

Another way that portal hypertension may influence lung vascular tone is that endotoxin, cytokines, or both, released from the splanchnic circulation, may bypass the liver and get into the lungs.19 Evidence in support of this is that patients with portosystemic shunting can develop similar pathologic changes in the pulmonary vascular bed that normalize when the shunt is reversed. To date, however, no substance has been definitively identified.

Yet another proposed mechanism is shear stress on the pulmonary endothelium from the hyperdynamic cardiac output, with resultant vascular remodeling; however, other mechanisms must be involved, as not everyone with liver disease develops portopulmonary hypertension (see below).

Krowka MJ, Edwards WD. A spectrum of pulmonary vascular pathology in portopulmonary hypertension. Liver Transplant 2000; 6:241–242. Copyright 2000. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley &amp; Sons, Inc.
Figure 1.
On autopsy, the small pulmonary arteries of patients with portopulmonary hypertension show various combinations of medial hypertrophy, endothelial and smooth muscle cell proliferation, fibrosis, and thrombosis (Figure 1).14,20 The thrombotic lesions are not due to abnormalities in coagulation but rather, possibly, to a combination of endothelial cell injury, platelet aggregation, and impaired blood flow.

These changes are identical to those in idiopathic and familial pulmonary arterial hypertension,21 and indeed, the World Health Organization now classifies portopulmonary hypertension in the same category as these primary forms of pulmonary hypertension rather than in the secondary forms.3

Why doesn’t everyone with liver disease develop portopulmonary hypertension?

The severity of liver disease or degree of portal hypertension does not appear to correlate with the severity of pulmonary hypertension,4 and portopulmonary hypertension does not develop in all patients with portal hypertension. Therefore, it is likely that some patients have a genetic or environmental susceptibility or suffer a “second hit” that triggers dysregulated pulmonary vascular proliferation and contributes to the development of pulmonary hypertension.

Whether genetic mutations play a role in portopulmonary hypertension remains unknown. Such a mutation could be similar to the one identified in the bone morphogenetic protein receptor type 2 gene (BMPR2) in familial pulmonary artery hypertension or the mutation in the activin-like kinase gene (ALK1) seen in pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.22

Current studies are investigating the role that bone-marrow-derived progenitor cells might play in the pathogenesis of portopulmonary hypertension.

CLINICAL FEATURES MAY NOT BE OBVIOUS AT FIRST

In the early stages of portopulmonary hypertension, patients may have no symptoms or only symptoms of liver disease, so it is important to have a high index of suspicion and screen for pulmonary hypertension. As its severity increases, symptoms may include fatigue, dyspnea, abdominal bloating, palpitations, chest pain or pressure, and syncope. The most common presenting symptom is dyspnea on exertion.

Similarly, the findings on physical examination also depend on the severity of pulmonary hypertension. Patients with mild portopulmonary hypertension may have only signs suggesting liver disease, such as spider telangiectases, jaundice, mild lower extremity edema, and ascites. As the severity of portopulmonary hypertension increases, however, findings of right heart pressure-and-volume overload become more obvious. These include peripheral edema, elevation of the jugular venous pressure, a right ventricular lift, a loud pulmonic valve closure, increased split of the second heart sound, a pulsatile liver, or a right-sided third or fourth heart sound.

 

 

SCREEN LIVER TRANSPLANT CANDIDATES

Screening for portopulmonary hypertension should be mandatory in patients undergoing evaluation for liver transplantation. This condition increases the risk of perioperative death, so it is not acceptable to make the diagnosis in the operating room!5

Electrocardiographic abnormalities that may raise the suspicion of portopulmonary hypertension include right atrial or ventricular enlargement and a right bundle branch pattern.

Chest radiographic signs are enlarged central pulmonary arteries and cardiomegaly. These electrocardiographic and radiographic signs tend to reflect advanced pulmonary hypertension.

Pulmonary function testing is not generally helpful, but the diffusing capacity may be decreased.

B-type natriuretic peptide (BNP) measurement may be helpful. BNP is released from the ventricles when the ventricles become dilated (due to pressure or volume overload), as in left or right heart failure. BNP testing is clinically useful in monitoring the severity of disease and the efficacy of treatment in patients with pulmonary hypertension; its role in portopulmonary hypertension requires prospective study.23

Transthoracic Doppler echocardiography is an excellent screening test and should be performed in patients undergoing evaluation for liver transplantation to exclude pulmonary hypertension.1 Findings on echocardiography that suggest portopulmonary hypertension include elevation of right ventricular systolic pressure (RVSP), which is calculated from the peak tricuspid regurgitant velocity (TRV) using the modified Bernoulli equation and an estimate of right atrial pressure (RAP):

RVSP = 4(TRV)2 + RAP.

Right atrial pressure is estimated from the filling characteristics of the inferior vena cava.

Transthoracic Doppler echocardiography has a sensitivity of 97% and a specificity of 77% in diagnosing moderate to severe pulmonary hypertension in patients undergoing evaluation for liver transplantation.24 Using an RVSP cutoff of 40 mm Hg, the sensitivity of Doppler echocardiography is about 80%, specificity 96%, positive predictive value 60%, and negative predictive value 98%.25

At Mayo Clinic, patients with an estimated RVSP greater than 50 mm Hg undergo right heart catheterization (see below). Such patients should also have repeat echocardiography at 1-year intervals to monitor for increasing pulmonary artery pressures5; for those on the waiting list for liver transplantation, the interval should probably be every 6 to 12 months.

RIGHT HEART CATHETERIZATION CONFIRMS THE DIAGNOSIS

The diagnosis of portopulmonary hypertension is confirmed with right heart catheterization to accurately measure pulmonary artery pressures, pulmonary artery occlusion pressure (to exclude volume overload), cardiac output (to exclude high-output pulmonary hypertension), and pulmonary vascular resistance. One study in patients with decompensated cirrhosis and refractory ascites found that a right atrial pressure of 14 mm Hg or greater had a positive predictive value of 83% for pulmonary hypertension.6

Other, potentially treatable causes of pulmonary hypertension must be excluded before diagnosing portopulmonary hypertension. These include thromboembolic disease, interstitial lung disease, connective tissue disease, untreated obstructive sleep apnea, and elevated pulmonary artery pressures due to increased cardiac output.

Vasodilator studies are being done less frequently in patients with portopulmonary hypertension, as they generally cannot tolerate calcium channel blocker therapy. Calcium channel blocker therapy is usually started in patients with idiopathic pulmonary artery hypertension who exhibit a positive vasodilator response. A positive vasodilator response also does not predict survival with or without liver transplantation. Unlike those with idiopathic pulmonary artery hypertension, many patients with portopulmonary hypertension cannot tolerate calcium channel blockers, as some of these drugs can exacerbate edema and portal hypertension.

GENERAL MANAGEMENT

Treatment of mild portopulmonary hypertension (mean pulmonary artery pressure < 35 mm Hg) is debatable. In these cases many patients do not have any symptoms attributable to portopulmonary hypertension, but only symptoms of liver disease, and they have a good functional status. As a group, such patients have not been formally studied to date.

Figure 2. Management algorithm for portopulmonary hypertension.
Patients with moderate to severe portopulmonary hypertension, however, may benefit from treatment aimed at improving symptoms and lowering pulmonary artery pressures and pulmonary vascular resistance (Figure 2).

Anticoagulation is often contraindicated in portopulmonary hypertension because of gastroesophageal varices, thrombocytopenia, or other coagulation abnormalities related to liver disease. If contraindications to anticoagulation do not exist, it should be considered.

Diuretics are a mainstay in the treatment of portopulmonary hypertension, both for the pulmonary hypertension and for the liver disease, especially if ascites or peripheral edema is present.

Oxygen should be given to patients with hypoxemia to keep the saturation greater than 90%.

Beta-blockers: A dilemma

Beta-blockers are used in many patients with liver disease as both primary and secondary prophylaxis of variceal bleeding.

However, one study has shown that in patients with moderate to severe portopulmonary hypertension, beta-blockers are associated with significant worsening of exercise capacity and pulmonary hemodynamic measurements.26 After beta-blockers were withdrawn, the 6-minute walking distance increased in 9 of 10 patients, and cardiac output increased with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance. The increases in cardiac output were related to a 25% increase in heart rate. Long-term follow-up was not reported, and it remains unclear whether rates of gastrointestinal bleeding may increase when beta-blockers are withdrawn.

Beta-blocker therapy in portopulmonary hypertension needs to be carefully considered and if at all possible should be avoided.

 

 

VASODILATOR THERAPY

Several vasodilating or vasomodulating drugs are available. However, much of the information about them comes from studies in patients with idiopathic pulmonary artery hypertension or pulmonary hypertension due to connective tissue disease, and no randomized controlled trials in portopulmonary hypertension have been performed.

Prostanoids

Prostanoids have been used successfully to lower pulmonary pressures in portopulmonary hypertension.

Epoprostenol (Flolan) is a pulmonary and systemic vasodilator as well as an inhibitor of platelet aggregation. It is given as a continuous intravenous infusion via an indwelling central venous catheter and a portable infusion pump. It has a very short half-life, requires mixing, and must be kept cold with ice packs, making it somewhat cumbersome to administer.

This medication has been shown to improve cardiopulmonary hemodynamics and exercise capacity in portopulmonary hypertension, although a survival advantage has not been documented to date.27 In several case series, some patients with portopulmonary hypertension treated with intravenous epoprostenol responded with a reduction in pulmonary pressures and successfully underwent liver transplantation.28–31

Complications of intravenous epoprostenol therapy include central venous catheter thrombosis, infection, and infusion pump failure; a backup pump must be available at all times. Patients with portopulmonary hypertension may also develop progressive splenomegaly and thrombocytopenia that may be due to increased blood flow in the splanchnic circulation.32

Treprostinil (Remodulin) has a longer half-life and does not have to be kept cold. It is given as a 24-hour intravenous or subcutaneous infusion, using an infusion pump that is smaller than that used with epoprostenol.

Although treprostinil is easier for patients to use, larger doses are necessary to achieve the same effect as with epoprostenol. With subcutaneous administration, the biggest drawback is site pain. Prostacyclin-related side effects include flushing, diarrhea, jaw discomfort, and lower extremity pain.

Iloprost (Ventavis) has the advantage of being given by inhalation. It is very short-acting, however, and requires six to nine inhalations per day.

Endothelin receptor blockers

Bosentan (Tracleer) is an oral agent that has been approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary hypertension, including in patients with portopulmonary hypertension who have mild hepatic derangement. This medication is a dual endothelin receptor antagonist, nonselectively blocking the endothelin A and B receptors on the endothelial and vascular smooth muscle cells so that ET-1 cannot bind and cause vasoconstriction.

In approximately 10% of patients, bosentan can cause elevations in aminotransferase, alkaline phosphatase, and bilirubin levels, which therefore must be checked monthly.33 Irreversible hepatic toxicity is uncommon; in most cases, liver function abnormalities return to baseline levels when the medication is stopped. The presumed mechanism is impairment of bile-salt transporters, leading to bile-salt accumulation in the liver.34 Bosentan’s use in patients with liver disease has not been well studied, although several case reports have described its use in patients with portopulmonary hypertension.35–38

Ambrisentan (Letairis) is a selective endothelin receptor-A blocker that has just received FDA approval for the treatment of pulmonary artery hypertension. It has not yet been studied in portopulmonary hypertension. Elevations in liver enzymes and bilirubin may also occur, and monthly monitoring is indicated.

Sildenafil

Another oral agent that might be effective in portopulmonary hypertension is sildenafil (Revatio). A phosphodiesterase-5 inhibitor, it selectively inhibits the cyclic guanosine monophosphatase-specific phosphodiesterase type 5 enzyme that is found in large concentrations in pulmonary artery smooth muscle cells.

In other forms of pulmonary hypertension, sildenafil has been shown to increase cardiac output and decrease pulmonary artery pressures and pulmonary vascular resistance without serious adverse events.39–41

In one reported case, treatment with sildenafil in a patient with portopulmonary hypertension decreased the mean pulmonary artery pressure from 56 mm Hg to 28 to 31 mm Hg, and the patient underwent successful liver transplantation.42 A recent case series of 14 patients with portopulmonary hypertension treated with sildenafil documents some improvement in 6-minute walking distance, suggesting that sildenafil as monotherapy or in combination therapy might be effective in portopulmonary hypertension.43 However, in 3 of these patients, the cardiac index decreased and pulmonary vascular resistance increased.44

We must emphasize that controlled studies in portopulmonary hypertension need to be done to find the optimal therapy.

 

 

LIVER TRANSPLANTATION MAY BENEFIT A FEW PATIENTS

Liver transplantation may be beneficial in highly selected patients with portopulmonary hypertension. However, this condition increases the risk of intraoperative and immediate postoperative complications of liver transplantation, so patients should be carefully evaluated5,45 at a liver transplantation center experienced in its management, including medical treatment with well-defined protocols regarding timing of liver transplantation.

Patients with mean pulmonary artery pressures greater than 50 mm Hg should not undergo liver transplantation. Those with mean pulmonary artery pressure between 35 and 50 mm Hg also have an increased mortality rate and may benefit from prolonged treatment for pulmonary hypertension.5,46

One successful case of living-related liver transplantation in a patient with portopulmonary hypertension has been published.47 (Most other successful transplants were from unrelated cadaver donors.)

Some patients who initially cannot undergo liver transplantation owing to severe pulmonary hypertension may eventually be able to do so if they receive medical therapy that improves their pulmonary hemodynamic profile, decreasing their mean pulmonary artery pressure and pulmonary vascular resistance. This would apply to a small subset of patients with portopulmonary hypertension.

When patients without pulmonary hypertension undergo liver transplantation, right ventricular function is preserved throughout all phases of the surgery.48 Patients with portopulmonary hypertension, however, may develop hemodynamic instability during liver transplantation. The most critical times are the induction of anesthesia, during and after graft reperfusion, and the immediate postoperative period.49,50

During the surgery, patients may require vasodilators if they have worsening pulmonary hypertension, or inotropic medications if they have right ventricular dysfunction and heart failure. In one study,51 eight patients with portopulmonary hypertension diagnosed at anesthesia induction for liver transplantation all required intraoperative vasodilator therapy after graft reperfusion because of marked increases in pulmonary artery pressures and pulmonary vascular resistance.

The increase in blood flow following reperfusion or necessary fluid challenges may exacerbate pulmonary hypertension, resulting in worsening right heart function and backup into the transplanted liver. Infusion of 1 liter of crystalloid over 10 minutes has been shown to increase mean pulmonary artery pressure and pulmonary artery occlusion pressure in liver transplantation candidates without pulmonary hypertension52; this response may be exaggerated in portopulmonary hypertension.

PROGNOSIS VARIES WITH SEVERITY OF DISEASE

The natural history of untreated portopulmonary hypertension varies with the degree of liver disease and the severity of pulmonary hypertension. Transplant-free survival was 85% at 1 year and 38% at 3 years in one study.45 The cardiac index appears to be the most significant prognostic variable.20

In a retrospective study of 78 patients with portopulmonary hypertension treated conservatively (before prostanoids were available) the median survival was 6 months (range 0–84 months) from the time of diagnosis.53 Causes of death included right heart failure, sudden death, gastrointestinal bleeding, and small bowel perforation.

Most of the data on outcomes of drug treatment and liver transplantation in patients with portopulmonary hypertension come from case series and retrospective reviews; prospective trials have been lacking.

If right ventricular function is normal and pulmonary hypertension is mild (mean pulmonary artery pressure < 35 mm Hg), patients tend to do well with liver transplantation.9

Outcomes are worse if pulmonary hypertension is more severe. In a database54 from 10 liver transplant centers from 1996 to 2001, 13 (36%) of 36 patients undergoing liver transplantation died in the hospital, emphasizing the importance of accurately assessing the severity of pulmonary hypertension before attempting liver transplantation.46 The rate was even higher—92%—in those with a mean pulmonary artery pressure greater than 35 mm Hg. The cause of death in severe pulmonary hypertension was failure of the right ventricle.

However, some patients with moderate to severe portopulmonary hypertension have been bridged with medications to lower pulmonary artery pressures and pulmonary vascular resistance so that liver transplantation can be safely done, and some have even been able to discontinue medications because their pulmonary hypertension resolved.29,31,41,42,47

Unlike in hepatopulmonary syndrome, liver transplantation is not the treatment of choice for portopulmonary hypertension, and pulmonary hypertension does not always resolve after liver transplantation. Many patients continue therapy for pulmonary hypertension after liver transplantation. Pulmonary hypertension may resolve, persist, or even develop de novo after liver transplantation.1 If pulmonary hypertension resolves, it does so over a prolonged time—months to years—favoring a vascular remodeling hypothesis as opposed to simply reversing vasoconstriction.

References
  1. Rodriguez-Roisin R, Krowka MJ, Hervé P, Fallon MB; ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 2004; 24:861880.
  2. Krowka MJ, Swanson KL, Frantz RP, et al. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 2006; 44:15021510.
  3. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:5S12S.
  4. Hadengue A, Benhayoun MK, Lebrec D, et al. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991; 100:520528.
  5. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transplant 2000; 6:443450.
  6. Benjaminov FS, Prentice M, Sniderman KW, et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:13551362.
  7. McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983; 127:437441.
  8. Cheng EY, Woehlck H. Pulmonary artery hypertension complicating anesthesia for liver transplantation. Anesthesiology 1992; 77:375378.
  9. Castro M, Krowka MJ, Schroeder DR, et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplantation. Mayo Clin Proc 1996; 71:543551.
  10. Ramsay MA, Simpson BR, Nguyen AT, et al. Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 1997; 3:494500.
  11. Kiely DG, Cargill RI, Struthers AD, et al. Cardiopulmonary effects of endothelin-1 in man. Cardiovasc Res 1997; 33:378386.
  12. Panos RJ, Baker SK. Mediators, cytokines, and growth factors in liver-lung interactions. Clin Chest Med 1996; 17:151169.
  13. Higgenbottam T. Pathophysiology of pulmonary hypertension. Chest 1994; 105:7S12S.
  14. Krowka MJ. Hepatopulmonary syndrome and portopulmonary hypertension: distinction and dilemmas. Hepatology 1997; 25:12821284.
  15. Hongqun L, Lee SS. Cardiopulmonary dysfunction in cirrhosis. Hepatology 2000; 14:600608.
  16. Lebrec D, Brenot F, Simonneau G, et al. Pulmonary arterial hypertension in portal hypertension. Eur Respir J 1998; 11:11531166.
  17. Herve P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in portal hypertension. Eur Respir J 1998; 11:11531166.
  18. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999; 159:19251932.
  19. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363:14611468.
  20. Edwards B, Weir K, Edwards WD, et al. Coexistent pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987; 10:12331238.
  21. Ramsay MAE, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 1997; 3:494500.
  22. Trembath RC. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345:325334.
  23. Leuchte HH, Holzapfel M, Baumgartner RA, et al. Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol 2004; 43:764770.
  24. Kim WR, Krowka MJ, Plevak DJ, et al. Accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in liver transplant candidates. Liver Transplant 2000; 6:453458.
  25. Colle IO, Moreau R, Godinho E, et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology 2003; 37:401409.
  26. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 2006; 130:120126.
  27. Swanson KL, McGoon MD, Krowka MJ. Survival in patients with portopulmonary hypertension [abstract]. Am J Respir Crit Care Med 2003; 167:A693.
  28. Kuo PC, Johnson LB, Plotkin JS, et al. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 1997; 63:604616.
  29. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999; 30:641648.
  30. Kähler CM, Graziadei I, Wiedermann CJ, Kneussl MP, Vogel W. Successful use of continuous intravenous prostacyclin in a patient with severe portopulmonary hypertension. Wien Klin Wochenschr 2000; 112:637640.
  31. Sussman N, Kaza V, Barshes N, et al. Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series. Am J Transplant 2006; 6:21772182.
  32. Findlay JY, Plevak DJ, Krowka MJ, et al. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transplant Surg 1999; 5:381387.
  33. Rubin LJ, Roux S. Bosentan: a dual endothelin receptor antagonist. Expert Opin Invest Drugs 2002; 11:9911002.
  34. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001; 69:223231.
  35. Hinterhuber L, Graziadei IW, Kahler CM, et al. Endothelin-receptor anatgonist treatment of portopulmonary hypertension. Clin Gastroenterol Hepatol 2004; 2:10391042.
  36. Clift PF, Townend JN, Bramhall S, et al. Successful treatment of severe portopulmonary hypertension after liver transplantation by bosentan. Transplantation 2004; 77:17741775.
  37. Halank M, Miehlke S, Hoeffken G, et al. Use of oral endothelin-receptor antagonist bosentan in the treatment of portopulmonary hypertension. Transplantation 2004; 77:17751776.
  38. Kuntzen C, Gulberg V, Gerbes AL. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Gastroenterology 2005; 128:164168.
  39. Watanabe H, Ohashi K, Takeuchi K, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002; 71:398402.
  40. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002; 105:23982403.
  41. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360:895900.
  42. Makisalo H, Koivusalo A, Vakkuri A, et al. Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation. Liver Transplant 2004; 10:945950.
  43. Reichengerger F, Voswinckel R, Steveling E, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J 2006; 28:563567.
  44. Krowka MJ, Swanson KL. How should we treat portopulmonary hypertension? Eur Respir J 2006; 28:466467.
  45. Kawut SM, Taichman DB, Ahya VN, et al. Hemodynamics and survival of patients with portopulmonary hypertension. Liver Transplant 2005; 11:11071111.
  46. Krowka MJ, Mandell MS, Ramsay MA, et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database. Liver Transplant 2004; 10:174182.
  47. Sulica R, Emre S, Poon M. Medical management of portopulmonary hypertension and right heart failure prior to living-related liver transplantation. Congest Heart Fail 2004; 10:192194.
  48. De Wolf AM, Begliomini B, Gasior TA, et al. Right ventricular function during orthotopic liver transplantation. Anesthes Analges 1993; 76:562568.
  49. Csete M. Intraoperative management of liver transplant patients with pulmonary hypertension. Liver Transplant Surg 1997; 3:454455.
  50. Acosta F, Sansano T, Palenciano CG, et al. Portopulmonary hypertension and liver transplantation: hemodynamic consequences at reperfusion. Transplant Proc 2005; 37:38653866.
  51. Taura P, Garcia-Valdecasas JC, Beltran J, et al. Moderate primary pulmonary hypertension in patients undergoing liver transplantation. Anesthes Analges 1996; 83:675680.
  52. Kuo PC, Schroeder RA, Vagelos RH, et al. Volume-mediated pulmonary responses in liver transplant candidates. Clin Transplant 1996; 10:521527.
  53. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991; 17:492498.
  54. Mandell MS, Krowka MJ. Formation of a national database on pulmonary hypertension and hepatopulmonary syndrome in chronic liver disease. Anesthesiology 1997; 87:450451.
References
  1. Rodriguez-Roisin R, Krowka MJ, Hervé P, Fallon MB; ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 2004; 24:861880.
  2. Krowka MJ, Swanson KL, Frantz RP, et al. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 2006; 44:15021510.
  3. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:5S12S.
  4. Hadengue A, Benhayoun MK, Lebrec D, et al. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991; 100:520528.
  5. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transplant 2000; 6:443450.
  6. Benjaminov FS, Prentice M, Sniderman KW, et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52:13551362.
  7. McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983; 127:437441.
  8. Cheng EY, Woehlck H. Pulmonary artery hypertension complicating anesthesia for liver transplantation. Anesthesiology 1992; 77:375378.
  9. Castro M, Krowka MJ, Schroeder DR, et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplantation. Mayo Clin Proc 1996; 71:543551.
  10. Ramsay MA, Simpson BR, Nguyen AT, et al. Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 1997; 3:494500.
  11. Kiely DG, Cargill RI, Struthers AD, et al. Cardiopulmonary effects of endothelin-1 in man. Cardiovasc Res 1997; 33:378386.
  12. Panos RJ, Baker SK. Mediators, cytokines, and growth factors in liver-lung interactions. Clin Chest Med 1996; 17:151169.
  13. Higgenbottam T. Pathophysiology of pulmonary hypertension. Chest 1994; 105:7S12S.
  14. Krowka MJ. Hepatopulmonary syndrome and portopulmonary hypertension: distinction and dilemmas. Hepatology 1997; 25:12821284.
  15. Hongqun L, Lee SS. Cardiopulmonary dysfunction in cirrhosis. Hepatology 2000; 14:600608.
  16. Lebrec D, Brenot F, Simonneau G, et al. Pulmonary arterial hypertension in portal hypertension. Eur Respir J 1998; 11:11531166.
  17. Herve P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in portal hypertension. Eur Respir J 1998; 11:11531166.
  18. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999; 159:19251932.
  19. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363:14611468.
  20. Edwards B, Weir K, Edwards WD, et al. Coexistent pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987; 10:12331238.
  21. Ramsay MAE, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 1997; 3:494500.
  22. Trembath RC. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345:325334.
  23. Leuchte HH, Holzapfel M, Baumgartner RA, et al. Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol 2004; 43:764770.
  24. Kim WR, Krowka MJ, Plevak DJ, et al. Accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in liver transplant candidates. Liver Transplant 2000; 6:453458.
  25. Colle IO, Moreau R, Godinho E, et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology 2003; 37:401409.
  26. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 2006; 130:120126.
  27. Swanson KL, McGoon MD, Krowka MJ. Survival in patients with portopulmonary hypertension [abstract]. Am J Respir Crit Care Med 2003; 167:A693.
  28. Kuo PC, Johnson LB, Plotkin JS, et al. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 1997; 63:604616.
  29. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999; 30:641648.
  30. Kähler CM, Graziadei I, Wiedermann CJ, Kneussl MP, Vogel W. Successful use of continuous intravenous prostacyclin in a patient with severe portopulmonary hypertension. Wien Klin Wochenschr 2000; 112:637640.
  31. Sussman N, Kaza V, Barshes N, et al. Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series. Am J Transplant 2006; 6:21772182.
  32. Findlay JY, Plevak DJ, Krowka MJ, et al. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transplant Surg 1999; 5:381387.
  33. Rubin LJ, Roux S. Bosentan: a dual endothelin receptor antagonist. Expert Opin Invest Drugs 2002; 11:9911002.
  34. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001; 69:223231.
  35. Hinterhuber L, Graziadei IW, Kahler CM, et al. Endothelin-receptor anatgonist treatment of portopulmonary hypertension. Clin Gastroenterol Hepatol 2004; 2:10391042.
  36. Clift PF, Townend JN, Bramhall S, et al. Successful treatment of severe portopulmonary hypertension after liver transplantation by bosentan. Transplantation 2004; 77:17741775.
  37. Halank M, Miehlke S, Hoeffken G, et al. Use of oral endothelin-receptor antagonist bosentan in the treatment of portopulmonary hypertension. Transplantation 2004; 77:17751776.
  38. Kuntzen C, Gulberg V, Gerbes AL. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Gastroenterology 2005; 128:164168.
  39. Watanabe H, Ohashi K, Takeuchi K, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002; 71:398402.
  40. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002; 105:23982403.
  41. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360:895900.
  42. Makisalo H, Koivusalo A, Vakkuri A, et al. Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation. Liver Transplant 2004; 10:945950.
  43. Reichengerger F, Voswinckel R, Steveling E, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J 2006; 28:563567.
  44. Krowka MJ, Swanson KL. How should we treat portopulmonary hypertension? Eur Respir J 2006; 28:466467.
  45. Kawut SM, Taichman DB, Ahya VN, et al. Hemodynamics and survival of patients with portopulmonary hypertension. Liver Transplant 2005; 11:11071111.
  46. Krowka MJ, Mandell MS, Ramsay MA, et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database. Liver Transplant 2004; 10:174182.
  47. Sulica R, Emre S, Poon M. Medical management of portopulmonary hypertension and right heart failure prior to living-related liver transplantation. Congest Heart Fail 2004; 10:192194.
  48. De Wolf AM, Begliomini B, Gasior TA, et al. Right ventricular function during orthotopic liver transplantation. Anesthes Analges 1993; 76:562568.
  49. Csete M. Intraoperative management of liver transplant patients with pulmonary hypertension. Liver Transplant Surg 1997; 3:454455.
  50. Acosta F, Sansano T, Palenciano CG, et al. Portopulmonary hypertension and liver transplantation: hemodynamic consequences at reperfusion. Transplant Proc 2005; 37:38653866.
  51. Taura P, Garcia-Valdecasas JC, Beltran J, et al. Moderate primary pulmonary hypertension in patients undergoing liver transplantation. Anesthes Analges 1996; 83:675680.
  52. Kuo PC, Schroeder RA, Vagelos RH, et al. Volume-mediated pulmonary responses in liver transplant candidates. Clin Transplant 1996; 10:521527.
  53. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991; 17:492498.
  54. Mandell MS, Krowka MJ. Formation of a national database on pulmonary hypertension and hepatopulmonary syndrome in chronic liver disease. Anesthesiology 1997; 87:450451.
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Page Number
121-122, 125-130, 133, 136
Page Number
121-122, 125-130, 133, 136
Publications
Publications
Topics
Article Type
Display Headline
Screen for portopulmonary hypertension, especially in liver transplant candidates
Display Headline
Screen for portopulmonary hypertension, especially in liver transplant candidates
Sections
Inside the Article

KEY POINTS

  • In portopulmonary hypertension, the pulmonary artery pressures, pulmonary vascular resistance, and portal venous pressure are all elevated.
  • All candidates for liver transplantation should undergo echocardiography to screen for portopulmonary hypertension. If the echocardiogram shows elevated pulmonary pressures, right heart catheterization must be performed to confirm the diagnosis.
  • The ideal medical regimen remains to be determined. Although drug treatment may lower pulmonary artery pressures in selected patients so that liver transplantation can be safely done, morbidity and mortality rates remain higher in patients with moderate to severe portopulmonary hypertension.
  • Liver transplantation is not the treatment of choice for portopulmonary hypertension.
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

Should all patients with chronic kidney disease take a statin?

Article Type
Changed
Mon, 04/16/2018 - 16:39
Display Headline
Should all patients with chronic kidney disease take a statin?

We think some patients with chronic kidney disease should take a statin, particularly those in stages 1 through 4 (ie, not yet on dialysis1)* who have low-density lipoprotein cholesterol (LDL-C) levels higher than 100 mg/dL. However, few studies have addressed this question.

*Stages of chronic kidney disease1:
Stage 1—kidney damage with normal or high glomerular filtration rate (GFR ≥ 90 mL/min/1.73 m2)
Stage 2—kidney damage with mildly decreased GFR (60–89 mL/min/1.73 m2)
Stage 3—moderately decreased GFR (30–59 mL/min/1.73 m2)
Stage 4—severely decreased GFR (15–29 mL/min/1.73 m2)
Stage 5—kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis)

The answer is murkier in patients on dialysis. Only one study has been done in this population, and it found no benefit from statin therapy. However, we would prescribe a statin for a dialysis patient who had known coronary artery disease and an LDL-C level higher than 100 mg/dL.

RATIONALE FOR STATIN USE: KIDNEY PATIENTS ARE AT RISK

Cardiovascular disease is common among patients with chronic kidney disease. While the risks of cardiovascular disease and death are highest among those requiring dialysis, earlier stages of chronic kidney disease also are associated with cardiovascular disease.2–4

The prevalence of traditional risk factors, particularly diabetes and hypertension, is high in all stages of kidney disease, and dyslipidemia is extremely common. Patients with chronic kidney disease who are not on dialysis tend to have lower levels of high-density lipoprotein cholesterol and higher levels of triglycerides, lipoprotein remnants, lipoprotein(a), and LDL-C. The lipid profile of dialysis patients is more complex, as malnutrition and inflammation in this population may lead to low cholesterol levels.

Since statins are effective for primary and secondary prevention of cardiovascular events in those in the general population with high LDL-C,5 we could expect that the same holds true for patients with chronic kidney disease. Furthermore, if kidney disease were considered a coronary heart disease equivalent, more than 85% of those with stage 3, 4, or 5 disease would qualify for lipid-lowering therapy by LDL-C criteria.6

However, compared with the large body of evidence in those without kidney disease, we have few data on the effect of statins on cardiovascular outcomes in those with kidney disease. Five of seven major trials of statins excluded patients with chronic kidney disease by using a creatinine cutoff or by excluding patients with known kidney disease.7

Renoprotective effects

Besides their cardiovascular effects, statins may slow the progression of kidney disease.

A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) trial8 showed a 12% increase in creatinine clearance in the group receiving atorvastatin (Lipitor) (P = .0001). In comparison, creatinine clearance decreased by 4% in the placebo group.

A subgroup analysis of the Cholesterol and Recurrent Events (CARE) trial, a secondary prevention trial of pravastatin (Pravachol) vs placebo, showed a similar effect for patients with a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 at baseline.9

A meta-analysis of 27 randomized trials (39,704 participants) concluded that, compared with no treatment, statins slowed the loss of GFR by a mean of 1.22 mL/min/year (95% confidence interval 0.44–2.0).10

Statins may confer this benefit independently of lipid-lowering. These drugs seem to decrease proteinuria, possibly by improving endothelial function or decreasing inflammation.11 A meta-analysis (1,384 patients) noted that 13 of 15 published studies found an antiproteinuric effect, with a greater effect in those with greater baseline proteinuria.12

The Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients With Progressive Renal Disease Trial (PLANET) will enroll 345 diabetic patients with protein-uria and hypercholesterolemia and examine the effects of rosuvastatin (Crestor) and atorvastatin on proteinuria and GFR.13

 

 

Cardioprotective effects in stages 1–4

Since patients with chronic kidney disease were excluded from most of the major statin trials, the best evidence in those with non-dialysis-dependent disease comes from post hoc analysis of data from the CARE study.14 While this trial excluded patients with more than 2+ proteinuria on dipstick analysis and those with creatinine values greater than 1.5 times the upper limit of normal, 1,711 of the initial 4,159 patients had a creatinine clearance of less than 75 mL/min; the mean creatinine clearance in this subgroup was 61. In this subgroup, pravastatin therapy was associated with a significantly lower risk of cardiovascular death or recurrent nonfatal myocardial infarction (MI) (hazard ratio 0.72, P < 0.05).

Similarly, in the 4,491 patients with chronic kidney disease (mean GFR 55 mL/min/1.73 m2) in the Pravastatin Pooling Project, the hazard of new MI, cardiovascular death, or cardiac intervention was nearly 25% lower in the pravastatin group.15

The ongoing Study of Heart and Renal Protection (SHARP),16 a randomized trial of ezetimibe/simvastatin (Vytorin) that enrolled 6,000 people with stages 3 to 4 kidney disease and 3,000 dialysis patients, will help in determining whether statin therapy prevents new vascular events. The study was launched in 2003 and has now completed enrollment. The primary outcome measure will be the time to first vascular event; secondary analyses will address whether statins decrease proteinuria or slow the progression of kidney disease.

Cardioprotective effects in dialysis patients

The only major randomized trial of statins ever conducted in dialysis patients with diabetes, the German Diabetes and Dialysis Study (4D), did not find atorvastatin 20 mg to have any benefit compared with placebo in reducing a composite end point of death from cardiac causes, stroke, and nonfatal MI over a median of 4 years of follow-up, despite a decrease in LDL-C of over 40% in the treatment group.17 Adverse events were similar in the two groups. The lack of a detectable benefit may be due to differences in the cardiovascular milieu in dialysis patients, who may have more advanced disease, with preexisting cardiac remodeling and congestive heart failure, which may not be modified to the same extent by statin therapy. Alternatively, the dose of atorvastatin may have been too low, or 4 years of treatment may not be sufficient to detect a benefit in these patients.

An ongoing prospective, randomized, placebo-controlled trial in 3,000 hemodialysis patients, called A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Haemodialysis: an Assessment of Survival and Cardiovascular Events (AURORA),18 will help to clarify the role of statins in this population.

CONCLUSION

The National Kidney Foundation guidelines1,19 note that people with chronic kidney disease are at high risk of cardiovascular disease and therefore should be treated according to guidelines for treating traditional risk factors in high-risk groups. We believe that those with dyslipidemia who are in stages 1 through 4, particularly those with other risk factors for coronary heart disease, should receive a statin, with an LDL-C target of less than 100 mg/dL, even though we have few data from large trials focused on this population and even though LDL-C may not be the only reason to consider statin use. The pleiotropic effects of statins on proteinuria and progression of kidney function loss may be of benefit in this population as well, although we would not recommend starting a statin solely for these effects until more data are available.

Despite the negative results of the 4D trial, given the relative safety of statins and the lack of any trial data suggesting harm in patients with chronic kidney disease, in our practice we treat dialysis patients with known cardiovascular disease with a statin, with a target LDL-C level less than 100 mg/dL. In dialysis patients without known cardiovascular disease, the use of a statin is even more controversial, and decisions should be made on an individual basis.

Results from the SHARP, AURORA, and PLANET trials, each of which is focused on patients with chronic kidney disease, will help determine whether statins benefit patients at this stage of disease.

References
  1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39 suppl 1:S1S266.
  2. Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005; 352:20492060.
  3. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32 suppl 3:S112S119.
  4. Manjunath G, Tighiouart H, Coresh J, et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003; 63:11211129.
  5. Baigent C, Keech A, Kearney PM, et al Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:12671278.
  6. Hyre AD, Fox CS, Astor BC, Cohen AJ, Muntner P. The impact of reclassifying moderate CKD as a coronary heart disease risk equivalent on the number of US adults recommended lipid-lowering treatment. Am J Kidney Dis 2007; 49:3745.
  7. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA 2006; 296:13771384.
  8. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004; 57:728734.
  9. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC Cholesterol and Recurrent Events Trial Investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003; 14:16051613.
  10. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol 2006; 17:20062016.
  11. Balk EM, Lau J, Goudas LC, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med 2003; 139:670682.
  12. Douglas K, O’Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006; 145:117124.
  13. US National Institutes of Health. Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease (PLANET 1). Accessed December 6, 2007. www.clinicaltrials.gov/ct/show/NCT00296374?order=1.
  14. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G Cholesterol and Recurrent Events (CARE) Trial Investigators. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003; 138:98104.
  15. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004; 110:15571563.
  16. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003; 84:S207S210.
  17. Wanner C, Krane V, Marz W, et al German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238248.
  18. Fellstrom BC, Holdaas H, Jardine AG. Why do we need a statin trial in hemodialysis patients? Kidney Int 2003; 84 suppl:S204S206.
  19. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007; 49 suppl 2:S12154.
Article PDF
Author and Disclosure Information

Dena Rifkin, MD
Division of Nephrology, Tufts-New England Medical Center, Boston, MA

Mark Sarnak, MD, MS
Division of Nephrology, Tufts-New England Medical Center; Associate Professor of Medicine, Tufts University School of Medicine, Boston, MA

Address: Dena Rifkin, MD, Tufts-New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111 [email protected]

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Publications
Topics
Page Number
118-120
Sections
Author and Disclosure Information

Dena Rifkin, MD
Division of Nephrology, Tufts-New England Medical Center, Boston, MA

Mark Sarnak, MD, MS
Division of Nephrology, Tufts-New England Medical Center; Associate Professor of Medicine, Tufts University School of Medicine, Boston, MA

Address: Dena Rifkin, MD, Tufts-New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111 [email protected]

Author and Disclosure Information

Dena Rifkin, MD
Division of Nephrology, Tufts-New England Medical Center, Boston, MA

Mark Sarnak, MD, MS
Division of Nephrology, Tufts-New England Medical Center; Associate Professor of Medicine, Tufts University School of Medicine, Boston, MA

Address: Dena Rifkin, MD, Tufts-New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111 [email protected]

Article PDF
Article PDF

We think some patients with chronic kidney disease should take a statin, particularly those in stages 1 through 4 (ie, not yet on dialysis1)* who have low-density lipoprotein cholesterol (LDL-C) levels higher than 100 mg/dL. However, few studies have addressed this question.

*Stages of chronic kidney disease1:
Stage 1—kidney damage with normal or high glomerular filtration rate (GFR ≥ 90 mL/min/1.73 m2)
Stage 2—kidney damage with mildly decreased GFR (60–89 mL/min/1.73 m2)
Stage 3—moderately decreased GFR (30–59 mL/min/1.73 m2)
Stage 4—severely decreased GFR (15–29 mL/min/1.73 m2)
Stage 5—kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis)

The answer is murkier in patients on dialysis. Only one study has been done in this population, and it found no benefit from statin therapy. However, we would prescribe a statin for a dialysis patient who had known coronary artery disease and an LDL-C level higher than 100 mg/dL.

RATIONALE FOR STATIN USE: KIDNEY PATIENTS ARE AT RISK

Cardiovascular disease is common among patients with chronic kidney disease. While the risks of cardiovascular disease and death are highest among those requiring dialysis, earlier stages of chronic kidney disease also are associated with cardiovascular disease.2–4

The prevalence of traditional risk factors, particularly diabetes and hypertension, is high in all stages of kidney disease, and dyslipidemia is extremely common. Patients with chronic kidney disease who are not on dialysis tend to have lower levels of high-density lipoprotein cholesterol and higher levels of triglycerides, lipoprotein remnants, lipoprotein(a), and LDL-C. The lipid profile of dialysis patients is more complex, as malnutrition and inflammation in this population may lead to low cholesterol levels.

Since statins are effective for primary and secondary prevention of cardiovascular events in those in the general population with high LDL-C,5 we could expect that the same holds true for patients with chronic kidney disease. Furthermore, if kidney disease were considered a coronary heart disease equivalent, more than 85% of those with stage 3, 4, or 5 disease would qualify for lipid-lowering therapy by LDL-C criteria.6

However, compared with the large body of evidence in those without kidney disease, we have few data on the effect of statins on cardiovascular outcomes in those with kidney disease. Five of seven major trials of statins excluded patients with chronic kidney disease by using a creatinine cutoff or by excluding patients with known kidney disease.7

Renoprotective effects

Besides their cardiovascular effects, statins may slow the progression of kidney disease.

A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) trial8 showed a 12% increase in creatinine clearance in the group receiving atorvastatin (Lipitor) (P = .0001). In comparison, creatinine clearance decreased by 4% in the placebo group.

A subgroup analysis of the Cholesterol and Recurrent Events (CARE) trial, a secondary prevention trial of pravastatin (Pravachol) vs placebo, showed a similar effect for patients with a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 at baseline.9

A meta-analysis of 27 randomized trials (39,704 participants) concluded that, compared with no treatment, statins slowed the loss of GFR by a mean of 1.22 mL/min/year (95% confidence interval 0.44–2.0).10

Statins may confer this benefit independently of lipid-lowering. These drugs seem to decrease proteinuria, possibly by improving endothelial function or decreasing inflammation.11 A meta-analysis (1,384 patients) noted that 13 of 15 published studies found an antiproteinuric effect, with a greater effect in those with greater baseline proteinuria.12

The Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients With Progressive Renal Disease Trial (PLANET) will enroll 345 diabetic patients with protein-uria and hypercholesterolemia and examine the effects of rosuvastatin (Crestor) and atorvastatin on proteinuria and GFR.13

 

 

Cardioprotective effects in stages 1–4

Since patients with chronic kidney disease were excluded from most of the major statin trials, the best evidence in those with non-dialysis-dependent disease comes from post hoc analysis of data from the CARE study.14 While this trial excluded patients with more than 2+ proteinuria on dipstick analysis and those with creatinine values greater than 1.5 times the upper limit of normal, 1,711 of the initial 4,159 patients had a creatinine clearance of less than 75 mL/min; the mean creatinine clearance in this subgroup was 61. In this subgroup, pravastatin therapy was associated with a significantly lower risk of cardiovascular death or recurrent nonfatal myocardial infarction (MI) (hazard ratio 0.72, P < 0.05).

Similarly, in the 4,491 patients with chronic kidney disease (mean GFR 55 mL/min/1.73 m2) in the Pravastatin Pooling Project, the hazard of new MI, cardiovascular death, or cardiac intervention was nearly 25% lower in the pravastatin group.15

The ongoing Study of Heart and Renal Protection (SHARP),16 a randomized trial of ezetimibe/simvastatin (Vytorin) that enrolled 6,000 people with stages 3 to 4 kidney disease and 3,000 dialysis patients, will help in determining whether statin therapy prevents new vascular events. The study was launched in 2003 and has now completed enrollment. The primary outcome measure will be the time to first vascular event; secondary analyses will address whether statins decrease proteinuria or slow the progression of kidney disease.

Cardioprotective effects in dialysis patients

The only major randomized trial of statins ever conducted in dialysis patients with diabetes, the German Diabetes and Dialysis Study (4D), did not find atorvastatin 20 mg to have any benefit compared with placebo in reducing a composite end point of death from cardiac causes, stroke, and nonfatal MI over a median of 4 years of follow-up, despite a decrease in LDL-C of over 40% in the treatment group.17 Adverse events were similar in the two groups. The lack of a detectable benefit may be due to differences in the cardiovascular milieu in dialysis patients, who may have more advanced disease, with preexisting cardiac remodeling and congestive heart failure, which may not be modified to the same extent by statin therapy. Alternatively, the dose of atorvastatin may have been too low, or 4 years of treatment may not be sufficient to detect a benefit in these patients.

An ongoing prospective, randomized, placebo-controlled trial in 3,000 hemodialysis patients, called A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Haemodialysis: an Assessment of Survival and Cardiovascular Events (AURORA),18 will help to clarify the role of statins in this population.

CONCLUSION

The National Kidney Foundation guidelines1,19 note that people with chronic kidney disease are at high risk of cardiovascular disease and therefore should be treated according to guidelines for treating traditional risk factors in high-risk groups. We believe that those with dyslipidemia who are in stages 1 through 4, particularly those with other risk factors for coronary heart disease, should receive a statin, with an LDL-C target of less than 100 mg/dL, even though we have few data from large trials focused on this population and even though LDL-C may not be the only reason to consider statin use. The pleiotropic effects of statins on proteinuria and progression of kidney function loss may be of benefit in this population as well, although we would not recommend starting a statin solely for these effects until more data are available.

Despite the negative results of the 4D trial, given the relative safety of statins and the lack of any trial data suggesting harm in patients with chronic kidney disease, in our practice we treat dialysis patients with known cardiovascular disease with a statin, with a target LDL-C level less than 100 mg/dL. In dialysis patients without known cardiovascular disease, the use of a statin is even more controversial, and decisions should be made on an individual basis.

Results from the SHARP, AURORA, and PLANET trials, each of which is focused on patients with chronic kidney disease, will help determine whether statins benefit patients at this stage of disease.

We think some patients with chronic kidney disease should take a statin, particularly those in stages 1 through 4 (ie, not yet on dialysis1)* who have low-density lipoprotein cholesterol (LDL-C) levels higher than 100 mg/dL. However, few studies have addressed this question.

*Stages of chronic kidney disease1:
Stage 1—kidney damage with normal or high glomerular filtration rate (GFR ≥ 90 mL/min/1.73 m2)
Stage 2—kidney damage with mildly decreased GFR (60–89 mL/min/1.73 m2)
Stage 3—moderately decreased GFR (30–59 mL/min/1.73 m2)
Stage 4—severely decreased GFR (15–29 mL/min/1.73 m2)
Stage 5—kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis)

The answer is murkier in patients on dialysis. Only one study has been done in this population, and it found no benefit from statin therapy. However, we would prescribe a statin for a dialysis patient who had known coronary artery disease and an LDL-C level higher than 100 mg/dL.

RATIONALE FOR STATIN USE: KIDNEY PATIENTS ARE AT RISK

Cardiovascular disease is common among patients with chronic kidney disease. While the risks of cardiovascular disease and death are highest among those requiring dialysis, earlier stages of chronic kidney disease also are associated with cardiovascular disease.2–4

The prevalence of traditional risk factors, particularly diabetes and hypertension, is high in all stages of kidney disease, and dyslipidemia is extremely common. Patients with chronic kidney disease who are not on dialysis tend to have lower levels of high-density lipoprotein cholesterol and higher levels of triglycerides, lipoprotein remnants, lipoprotein(a), and LDL-C. The lipid profile of dialysis patients is more complex, as malnutrition and inflammation in this population may lead to low cholesterol levels.

Since statins are effective for primary and secondary prevention of cardiovascular events in those in the general population with high LDL-C,5 we could expect that the same holds true for patients with chronic kidney disease. Furthermore, if kidney disease were considered a coronary heart disease equivalent, more than 85% of those with stage 3, 4, or 5 disease would qualify for lipid-lowering therapy by LDL-C criteria.6

However, compared with the large body of evidence in those without kidney disease, we have few data on the effect of statins on cardiovascular outcomes in those with kidney disease. Five of seven major trials of statins excluded patients with chronic kidney disease by using a creatinine cutoff or by excluding patients with known kidney disease.7

Renoprotective effects

Besides their cardiovascular effects, statins may slow the progression of kidney disease.

A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) trial8 showed a 12% increase in creatinine clearance in the group receiving atorvastatin (Lipitor) (P = .0001). In comparison, creatinine clearance decreased by 4% in the placebo group.

A subgroup analysis of the Cholesterol and Recurrent Events (CARE) trial, a secondary prevention trial of pravastatin (Pravachol) vs placebo, showed a similar effect for patients with a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 at baseline.9

A meta-analysis of 27 randomized trials (39,704 participants) concluded that, compared with no treatment, statins slowed the loss of GFR by a mean of 1.22 mL/min/year (95% confidence interval 0.44–2.0).10

Statins may confer this benefit independently of lipid-lowering. These drugs seem to decrease proteinuria, possibly by improving endothelial function or decreasing inflammation.11 A meta-analysis (1,384 patients) noted that 13 of 15 published studies found an antiproteinuric effect, with a greater effect in those with greater baseline proteinuria.12

The Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients With Progressive Renal Disease Trial (PLANET) will enroll 345 diabetic patients with protein-uria and hypercholesterolemia and examine the effects of rosuvastatin (Crestor) and atorvastatin on proteinuria and GFR.13

 

 

Cardioprotective effects in stages 1–4

Since patients with chronic kidney disease were excluded from most of the major statin trials, the best evidence in those with non-dialysis-dependent disease comes from post hoc analysis of data from the CARE study.14 While this trial excluded patients with more than 2+ proteinuria on dipstick analysis and those with creatinine values greater than 1.5 times the upper limit of normal, 1,711 of the initial 4,159 patients had a creatinine clearance of less than 75 mL/min; the mean creatinine clearance in this subgroup was 61. In this subgroup, pravastatin therapy was associated with a significantly lower risk of cardiovascular death or recurrent nonfatal myocardial infarction (MI) (hazard ratio 0.72, P < 0.05).

Similarly, in the 4,491 patients with chronic kidney disease (mean GFR 55 mL/min/1.73 m2) in the Pravastatin Pooling Project, the hazard of new MI, cardiovascular death, or cardiac intervention was nearly 25% lower in the pravastatin group.15

The ongoing Study of Heart and Renal Protection (SHARP),16 a randomized trial of ezetimibe/simvastatin (Vytorin) that enrolled 6,000 people with stages 3 to 4 kidney disease and 3,000 dialysis patients, will help in determining whether statin therapy prevents new vascular events. The study was launched in 2003 and has now completed enrollment. The primary outcome measure will be the time to first vascular event; secondary analyses will address whether statins decrease proteinuria or slow the progression of kidney disease.

Cardioprotective effects in dialysis patients

The only major randomized trial of statins ever conducted in dialysis patients with diabetes, the German Diabetes and Dialysis Study (4D), did not find atorvastatin 20 mg to have any benefit compared with placebo in reducing a composite end point of death from cardiac causes, stroke, and nonfatal MI over a median of 4 years of follow-up, despite a decrease in LDL-C of over 40% in the treatment group.17 Adverse events were similar in the two groups. The lack of a detectable benefit may be due to differences in the cardiovascular milieu in dialysis patients, who may have more advanced disease, with preexisting cardiac remodeling and congestive heart failure, which may not be modified to the same extent by statin therapy. Alternatively, the dose of atorvastatin may have been too low, or 4 years of treatment may not be sufficient to detect a benefit in these patients.

An ongoing prospective, randomized, placebo-controlled trial in 3,000 hemodialysis patients, called A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Haemodialysis: an Assessment of Survival and Cardiovascular Events (AURORA),18 will help to clarify the role of statins in this population.

CONCLUSION

The National Kidney Foundation guidelines1,19 note that people with chronic kidney disease are at high risk of cardiovascular disease and therefore should be treated according to guidelines for treating traditional risk factors in high-risk groups. We believe that those with dyslipidemia who are in stages 1 through 4, particularly those with other risk factors for coronary heart disease, should receive a statin, with an LDL-C target of less than 100 mg/dL, even though we have few data from large trials focused on this population and even though LDL-C may not be the only reason to consider statin use. The pleiotropic effects of statins on proteinuria and progression of kidney function loss may be of benefit in this population as well, although we would not recommend starting a statin solely for these effects until more data are available.

Despite the negative results of the 4D trial, given the relative safety of statins and the lack of any trial data suggesting harm in patients with chronic kidney disease, in our practice we treat dialysis patients with known cardiovascular disease with a statin, with a target LDL-C level less than 100 mg/dL. In dialysis patients without known cardiovascular disease, the use of a statin is even more controversial, and decisions should be made on an individual basis.

Results from the SHARP, AURORA, and PLANET trials, each of which is focused on patients with chronic kidney disease, will help determine whether statins benefit patients at this stage of disease.

References
  1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39 suppl 1:S1S266.
  2. Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005; 352:20492060.
  3. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32 suppl 3:S112S119.
  4. Manjunath G, Tighiouart H, Coresh J, et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003; 63:11211129.
  5. Baigent C, Keech A, Kearney PM, et al Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:12671278.
  6. Hyre AD, Fox CS, Astor BC, Cohen AJ, Muntner P. The impact of reclassifying moderate CKD as a coronary heart disease risk equivalent on the number of US adults recommended lipid-lowering treatment. Am J Kidney Dis 2007; 49:3745.
  7. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA 2006; 296:13771384.
  8. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004; 57:728734.
  9. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC Cholesterol and Recurrent Events Trial Investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003; 14:16051613.
  10. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol 2006; 17:20062016.
  11. Balk EM, Lau J, Goudas LC, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med 2003; 139:670682.
  12. Douglas K, O’Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006; 145:117124.
  13. US National Institutes of Health. Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease (PLANET 1). Accessed December 6, 2007. www.clinicaltrials.gov/ct/show/NCT00296374?order=1.
  14. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G Cholesterol and Recurrent Events (CARE) Trial Investigators. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003; 138:98104.
  15. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004; 110:15571563.
  16. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003; 84:S207S210.
  17. Wanner C, Krane V, Marz W, et al German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238248.
  18. Fellstrom BC, Holdaas H, Jardine AG. Why do we need a statin trial in hemodialysis patients? Kidney Int 2003; 84 suppl:S204S206.
  19. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007; 49 suppl 2:S12154.
References
  1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39 suppl 1:S1S266.
  2. Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005; 352:20492060.
  3. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32 suppl 3:S112S119.
  4. Manjunath G, Tighiouart H, Coresh J, et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003; 63:11211129.
  5. Baigent C, Keech A, Kearney PM, et al Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:12671278.
  6. Hyre AD, Fox CS, Astor BC, Cohen AJ, Muntner P. The impact of reclassifying moderate CKD as a coronary heart disease risk equivalent on the number of US adults recommended lipid-lowering treatment. Am J Kidney Dis 2007; 49:3745.
  7. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA 2006; 296:13771384.
  8. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004; 57:728734.
  9. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC Cholesterol and Recurrent Events Trial Investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003; 14:16051613.
  10. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol 2006; 17:20062016.
  11. Balk EM, Lau J, Goudas LC, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med 2003; 139:670682.
  12. Douglas K, O’Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006; 145:117124.
  13. US National Institutes of Health. Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease (PLANET 1). Accessed December 6, 2007. www.clinicaltrials.gov/ct/show/NCT00296374?order=1.
  14. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G Cholesterol and Recurrent Events (CARE) Trial Investigators. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003; 138:98104.
  15. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004; 110:15571563.
  16. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003; 84:S207S210.
  17. Wanner C, Krane V, Marz W, et al German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238248.
  18. Fellstrom BC, Holdaas H, Jardine AG. Why do we need a statin trial in hemodialysis patients? Kidney Int 2003; 84 suppl:S204S206.
  19. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007; 49 suppl 2:S12154.
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Page Number
118-120
Page Number
118-120
Publications
Publications
Topics
Article Type
Display Headline
Should all patients with chronic kidney disease take a statin?
Display Headline
Should all patients with chronic kidney disease take a statin?
Sections
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

Infective endocarditis prophylaxis before dental procedures: New guidelines spark controversy

Article Type
Changed
Mon, 04/16/2018 - 14:47
Display Headline
Infective endocarditis prophylaxis before dental procedures: New guidelines spark controversy

Many fewer people will need to receive antibiotics as prophylaxis against infective endocarditis before undergoing dental procedures, according to new guidelines released by the American Heart Association.1 Now, the only patients to receive antibiotics will be those at highest risk, ie, those with a prosthetic heart valve, a history of endocarditis, certain forms of congenital heart disease, or valvulopathy after heart transplantation, and only before certain dental procedures.

Unfortunately, these guidelines are still based largely on expert opinion, with very little hard evidence to show that antibiotic therapy actually prevents infective endocarditis. Nevertheless, the new guidelines appear reasonable, and we believe they should be followed.

A RARE BUT LIFE-THREATENING INFECTION

Infective endocarditis is a rare but life-threatening infection, with an incidence in the United States of 10,000 to 20,000 new cases per year. Mortality rates for both native-valve endocarditis and prosthetic-valve endocarditis range from 20% to 30%.2,3 For the past half-century, antibiotic prophylaxis for dental procedures has been recommended for patients judged to be at risk of infective endocarditis, in hopes of preventing this dreaded infectious disease.

ENDOCARDIAL INJURY, THEN BACTERIAL SEEDING

A combination of events must occur to cause infective endocarditis. First, injury to the endocardial surface induces focal adherence of platelets and fibrin. Then, a bacteremic event seeds this aggregate with microorganisms, attracting more platelets and fibrin, allowing uninhibited microbial growth and the development of an inflammatory plaque or vegetation.

The magnitude and duration of bacteremia that produces this cascade of events is uncertain. Transient bacteremia occurs commonly, not only during procedures that cause trauma to mucosal surfaces or tissue but also with daily activities such as brushing teeth and chewing. The reported incidence of bacteremia during dental intervention ranges from 10% to 100%, and with daily brushing and flossing, from 20% to 68%.1

STAPHYLOCOCCI OVERTAKING VIRIDANS STREPTOCOCCI AS CAUSE

While historically the viridans group of streptococci has been responsible for the largest percentage of cases of both native-valve endocarditis and late-onset prosthetic-valve endocarditis, times have changed. In more recently reported series, Staphylococcus aureus appears more common, and unlikely to be susceptible to antibiotics recommended for dental prophylaxis. Other causative pathogens include coagulase-negative staphylococci, enterococci, gram-negative microorganisms, and fungi.

PREVIOUS GUIDELINES—1997

Previous American Heart Association guidelines4 separated patients into three risk categories for infective endocarditis. High-risk patients were those with prosthetic heart valves, a history of infective endocarditis, complex cyanotic congenital heart disease, or surgically constructed systemic pulmonary shunts. Moderate-risk patients had other congenital cardiac defects, hypertrophic cardiomyopathy, or acquired valvular heart disease including mitral valve prolapse with regurgitation. Negligible-risk patients—ie, most patients—included those with coronary artery bypass grafts, a permanent pacemaker, or mitral valve prolapse without regurgitation. Antibiotic prophylaxis was recommended only for patients in the high-risk and moderate-risk groups.

 

 

THOUGHTS AND CHALLENGES

Although prophylaxis has been a standard practice for years, its efficacy and cost-effectiveness have never been proven, owing to a lack of prospective randomized controlled trials. A sequential relationship between dental procedures and infective endocarditis can be demonstrated in only 4% to 7.5% of cases.5 Most cases of infective endocarditis are not preceded by dental procedures.

Furthermore, the data are limited and insufficient to substantiate the efficacy of antibiotics in preventing endocarditis in patients with high-risk cardiac conditions who undergo dental procedures.6 Failures have occurred even when the infecting microorganism was susceptible to the antibiotic given for prophylaxis. Since bacteremia occurs also during brushing and flossing of teeth, why give prophylaxis just for dental procedures? Moreover, the risks of causing adverse or anaphylactic reactions from antibiotics, as well as contributing to the nationwide antibiotic resistance problem, are issues not to be taken lightly.

Poor compliance with prophylaxis has been documented. Studies by Duval et al7 and others have shown that practitioners adhere to recommended dental prophylaxis programs only about 40% of the time, while only 22% of patients with predisposing cardiac conditions could recall taking their prescribed prophylactic antibiotics before an indicated procedure, as recommended.8

NEW GUIDELINES—2007

To address many of these concerns, the American Heart Association1 released extensively revised guidelines in 2007. They are more pragmatic, narrowly focused for a selected group of patients who have a greater lifetime risk of illness and death from infective endocarditis.

The experts who wrote the guidelines agreed that evidence remains poor about which dental procedures increase the risk of infective endocarditis and the efficacy of antibiotic prophylaxis to prevent its development. They stress the importance of good oral hygiene and prevention of dental disease and argue persuasively that this will have a greater impact on decreasing the lifetime risk of infective endocarditis than will antibiotic prophylaxis.

Prophylaxis is now recommended only for patients with a prosthetic heart valve, a history of infective endocarditis, certain forms of congenital heart disease, and valvulopathy after cardiac transplantation (Table 1), and only before procedures that involve manipulation of gingival tissue or the periapical region of teeth, or perforation of the oral mucosa. Excluded are routine dental cleaning and anesthetic injections through noninfected tissue, dental radiography, placement and adjustment of appliances, shedding of deciduous teeth, and bleeding from trauma to the lips.

Regimens for dental prophylaxis should always be given 30 to 60 minutes before the procedure. Oral amoxicillin remains the drug of choice, and, for patients unable to take oral medications, ampicillin, cefazolin, or ceftriaxone can be used, either intramuscularly or intravenously (Table 2). For penicillin-allergic patients, oral cephalaxin, clindamycin, azithromycin, or clarithromycin is recommended, and, for patients unable to take oral antibiotics, cefazolin, ceftriaxone, or clindamycin, intramuscularly or intravenously.

CONTROVERSY WILL CONTINUE

The new guidelines for dental prophylaxis have been extensively revised and simplified. They are now focused only on patients who have a greater lifetime risk of illness and death from infective endocarditis. But what about patients who had previously been advised to take prophylaxis, such as those with mitral valve prolapse with regurgitation, who will not receive prophylaxis any more?

These guidelines will likely stir emotions, not only for practitioners who have strong desires to practice preventive medicine, but also for patients who have been taking prophylaxis in good faith per previous guidelines. They may feel abandoned. Unfortunately, funding for a prospective randomized clinical trial large enough to prove that antibiotic prophylaxis for dental procedures benefits patients is unlikely. That leaves us with the current recommendations, which are based on scientific evidence that currently exists and on expert opinion.

The intention of the guidelines is laudable. Of course, there will continue to be controversies with the new rules. Nevertheless, we believe they should be followed until there is more persuasive evidence to the contrary.

References
  1. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:17361754.
  2. Hill EE, Herligers P, Claus P, Vanderschueren S, Herregods MC, Peetermans WE. Infective endocarditis: changing epidemiology and predictors of 6-month mortality: a prospective cohort study. Eur Heart J 2007; 28:196203.
  3. Wang A, Athan E, Pappas PA, et al International Collaboration on Endocarditis-Prospective Cohort Study Investigators. Contemporary clinical profile and outcome of prosthetic valve endocarditis. JAMA 2007; 297:13541361.
  4. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997; 277:17941801.
  5. Gendron R, Grenier D, Maheu-Robert LF. The oral cavity as a reservoir of bacterial pathogens for focal infections. Microbes Infect 2000; 2:897906.
  6. Strom BL, Abrutyn E, Berlin JA, et al. Dental and cardiac risk factors for infective endocarditis. A population-based, case-control study. Ann Intern Med 1998; 129:761769.
  7. Duval X, Alla F, Hoen B, et al. Estimated risk of endocarditis in adults with predisposing cardiac conditions undergoing dental procedures with or without antibiotic prophylaxis. Clin Infect Dis 2006; 42:e102e107.
  8. van der Meer JT, van Wijk W, Thompson J, Valkenburg HA, Michel MF. Awareness of need and actual use of prophylaxis: lack of patient compliance in the prevention of bacterial endocarditis. J Antimicrob Chemother 1992; 29:187194.
Article PDF
Author and Disclosure Information

Alice Kim, MD
Department of Infective Diseases, Cleveland Clinic

Thomas Keys, MD
Department of Infective Diseases, Cleveland Clinic

Address: Alice Kim, MD, Department of Infectious Diseases, S32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195.

Dr. Keys has indicated that he has received royalties from Professional Communications, Inc., for editing a booklet on antimicrobial guidelines.

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Publications
Topics
Page Number
89-92
Sections
Author and Disclosure Information

Alice Kim, MD
Department of Infective Diseases, Cleveland Clinic

Thomas Keys, MD
Department of Infective Diseases, Cleveland Clinic

Address: Alice Kim, MD, Department of Infectious Diseases, S32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195.

Dr. Keys has indicated that he has received royalties from Professional Communications, Inc., for editing a booklet on antimicrobial guidelines.

Author and Disclosure Information

Alice Kim, MD
Department of Infective Diseases, Cleveland Clinic

Thomas Keys, MD
Department of Infective Diseases, Cleveland Clinic

Address: Alice Kim, MD, Department of Infectious Diseases, S32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195.

Dr. Keys has indicated that he has received royalties from Professional Communications, Inc., for editing a booklet on antimicrobial guidelines.

Article PDF
Article PDF
Related Articles

Many fewer people will need to receive antibiotics as prophylaxis against infective endocarditis before undergoing dental procedures, according to new guidelines released by the American Heart Association.1 Now, the only patients to receive antibiotics will be those at highest risk, ie, those with a prosthetic heart valve, a history of endocarditis, certain forms of congenital heart disease, or valvulopathy after heart transplantation, and only before certain dental procedures.

Unfortunately, these guidelines are still based largely on expert opinion, with very little hard evidence to show that antibiotic therapy actually prevents infective endocarditis. Nevertheless, the new guidelines appear reasonable, and we believe they should be followed.

A RARE BUT LIFE-THREATENING INFECTION

Infective endocarditis is a rare but life-threatening infection, with an incidence in the United States of 10,000 to 20,000 new cases per year. Mortality rates for both native-valve endocarditis and prosthetic-valve endocarditis range from 20% to 30%.2,3 For the past half-century, antibiotic prophylaxis for dental procedures has been recommended for patients judged to be at risk of infective endocarditis, in hopes of preventing this dreaded infectious disease.

ENDOCARDIAL INJURY, THEN BACTERIAL SEEDING

A combination of events must occur to cause infective endocarditis. First, injury to the endocardial surface induces focal adherence of platelets and fibrin. Then, a bacteremic event seeds this aggregate with microorganisms, attracting more platelets and fibrin, allowing uninhibited microbial growth and the development of an inflammatory plaque or vegetation.

The magnitude and duration of bacteremia that produces this cascade of events is uncertain. Transient bacteremia occurs commonly, not only during procedures that cause trauma to mucosal surfaces or tissue but also with daily activities such as brushing teeth and chewing. The reported incidence of bacteremia during dental intervention ranges from 10% to 100%, and with daily brushing and flossing, from 20% to 68%.1

STAPHYLOCOCCI OVERTAKING VIRIDANS STREPTOCOCCI AS CAUSE

While historically the viridans group of streptococci has been responsible for the largest percentage of cases of both native-valve endocarditis and late-onset prosthetic-valve endocarditis, times have changed. In more recently reported series, Staphylococcus aureus appears more common, and unlikely to be susceptible to antibiotics recommended for dental prophylaxis. Other causative pathogens include coagulase-negative staphylococci, enterococci, gram-negative microorganisms, and fungi.

PREVIOUS GUIDELINES—1997

Previous American Heart Association guidelines4 separated patients into three risk categories for infective endocarditis. High-risk patients were those with prosthetic heart valves, a history of infective endocarditis, complex cyanotic congenital heart disease, or surgically constructed systemic pulmonary shunts. Moderate-risk patients had other congenital cardiac defects, hypertrophic cardiomyopathy, or acquired valvular heart disease including mitral valve prolapse with regurgitation. Negligible-risk patients—ie, most patients—included those with coronary artery bypass grafts, a permanent pacemaker, or mitral valve prolapse without regurgitation. Antibiotic prophylaxis was recommended only for patients in the high-risk and moderate-risk groups.

 

 

THOUGHTS AND CHALLENGES

Although prophylaxis has been a standard practice for years, its efficacy and cost-effectiveness have never been proven, owing to a lack of prospective randomized controlled trials. A sequential relationship between dental procedures and infective endocarditis can be demonstrated in only 4% to 7.5% of cases.5 Most cases of infective endocarditis are not preceded by dental procedures.

Furthermore, the data are limited and insufficient to substantiate the efficacy of antibiotics in preventing endocarditis in patients with high-risk cardiac conditions who undergo dental procedures.6 Failures have occurred even when the infecting microorganism was susceptible to the antibiotic given for prophylaxis. Since bacteremia occurs also during brushing and flossing of teeth, why give prophylaxis just for dental procedures? Moreover, the risks of causing adverse or anaphylactic reactions from antibiotics, as well as contributing to the nationwide antibiotic resistance problem, are issues not to be taken lightly.

Poor compliance with prophylaxis has been documented. Studies by Duval et al7 and others have shown that practitioners adhere to recommended dental prophylaxis programs only about 40% of the time, while only 22% of patients with predisposing cardiac conditions could recall taking their prescribed prophylactic antibiotics before an indicated procedure, as recommended.8

NEW GUIDELINES—2007

To address many of these concerns, the American Heart Association1 released extensively revised guidelines in 2007. They are more pragmatic, narrowly focused for a selected group of patients who have a greater lifetime risk of illness and death from infective endocarditis.

The experts who wrote the guidelines agreed that evidence remains poor about which dental procedures increase the risk of infective endocarditis and the efficacy of antibiotic prophylaxis to prevent its development. They stress the importance of good oral hygiene and prevention of dental disease and argue persuasively that this will have a greater impact on decreasing the lifetime risk of infective endocarditis than will antibiotic prophylaxis.

Prophylaxis is now recommended only for patients with a prosthetic heart valve, a history of infective endocarditis, certain forms of congenital heart disease, and valvulopathy after cardiac transplantation (Table 1), and only before procedures that involve manipulation of gingival tissue or the periapical region of teeth, or perforation of the oral mucosa. Excluded are routine dental cleaning and anesthetic injections through noninfected tissue, dental radiography, placement and adjustment of appliances, shedding of deciduous teeth, and bleeding from trauma to the lips.

Regimens for dental prophylaxis should always be given 30 to 60 minutes before the procedure. Oral amoxicillin remains the drug of choice, and, for patients unable to take oral medications, ampicillin, cefazolin, or ceftriaxone can be used, either intramuscularly or intravenously (Table 2). For penicillin-allergic patients, oral cephalaxin, clindamycin, azithromycin, or clarithromycin is recommended, and, for patients unable to take oral antibiotics, cefazolin, ceftriaxone, or clindamycin, intramuscularly or intravenously.

CONTROVERSY WILL CONTINUE

The new guidelines for dental prophylaxis have been extensively revised and simplified. They are now focused only on patients who have a greater lifetime risk of illness and death from infective endocarditis. But what about patients who had previously been advised to take prophylaxis, such as those with mitral valve prolapse with regurgitation, who will not receive prophylaxis any more?

These guidelines will likely stir emotions, not only for practitioners who have strong desires to practice preventive medicine, but also for patients who have been taking prophylaxis in good faith per previous guidelines. They may feel abandoned. Unfortunately, funding for a prospective randomized clinical trial large enough to prove that antibiotic prophylaxis for dental procedures benefits patients is unlikely. That leaves us with the current recommendations, which are based on scientific evidence that currently exists and on expert opinion.

The intention of the guidelines is laudable. Of course, there will continue to be controversies with the new rules. Nevertheless, we believe they should be followed until there is more persuasive evidence to the contrary.

Many fewer people will need to receive antibiotics as prophylaxis against infective endocarditis before undergoing dental procedures, according to new guidelines released by the American Heart Association.1 Now, the only patients to receive antibiotics will be those at highest risk, ie, those with a prosthetic heart valve, a history of endocarditis, certain forms of congenital heart disease, or valvulopathy after heart transplantation, and only before certain dental procedures.

Unfortunately, these guidelines are still based largely on expert opinion, with very little hard evidence to show that antibiotic therapy actually prevents infective endocarditis. Nevertheless, the new guidelines appear reasonable, and we believe they should be followed.

A RARE BUT LIFE-THREATENING INFECTION

Infective endocarditis is a rare but life-threatening infection, with an incidence in the United States of 10,000 to 20,000 new cases per year. Mortality rates for both native-valve endocarditis and prosthetic-valve endocarditis range from 20% to 30%.2,3 For the past half-century, antibiotic prophylaxis for dental procedures has been recommended for patients judged to be at risk of infective endocarditis, in hopes of preventing this dreaded infectious disease.

ENDOCARDIAL INJURY, THEN BACTERIAL SEEDING

A combination of events must occur to cause infective endocarditis. First, injury to the endocardial surface induces focal adherence of platelets and fibrin. Then, a bacteremic event seeds this aggregate with microorganisms, attracting more platelets and fibrin, allowing uninhibited microbial growth and the development of an inflammatory plaque or vegetation.

The magnitude and duration of bacteremia that produces this cascade of events is uncertain. Transient bacteremia occurs commonly, not only during procedures that cause trauma to mucosal surfaces or tissue but also with daily activities such as brushing teeth and chewing. The reported incidence of bacteremia during dental intervention ranges from 10% to 100%, and with daily brushing and flossing, from 20% to 68%.1

STAPHYLOCOCCI OVERTAKING VIRIDANS STREPTOCOCCI AS CAUSE

While historically the viridans group of streptococci has been responsible for the largest percentage of cases of both native-valve endocarditis and late-onset prosthetic-valve endocarditis, times have changed. In more recently reported series, Staphylococcus aureus appears more common, and unlikely to be susceptible to antibiotics recommended for dental prophylaxis. Other causative pathogens include coagulase-negative staphylococci, enterococci, gram-negative microorganisms, and fungi.

PREVIOUS GUIDELINES—1997

Previous American Heart Association guidelines4 separated patients into three risk categories for infective endocarditis. High-risk patients were those with prosthetic heart valves, a history of infective endocarditis, complex cyanotic congenital heart disease, or surgically constructed systemic pulmonary shunts. Moderate-risk patients had other congenital cardiac defects, hypertrophic cardiomyopathy, or acquired valvular heart disease including mitral valve prolapse with regurgitation. Negligible-risk patients—ie, most patients—included those with coronary artery bypass grafts, a permanent pacemaker, or mitral valve prolapse without regurgitation. Antibiotic prophylaxis was recommended only for patients in the high-risk and moderate-risk groups.

 

 

THOUGHTS AND CHALLENGES

Although prophylaxis has been a standard practice for years, its efficacy and cost-effectiveness have never been proven, owing to a lack of prospective randomized controlled trials. A sequential relationship between dental procedures and infective endocarditis can be demonstrated in only 4% to 7.5% of cases.5 Most cases of infective endocarditis are not preceded by dental procedures.

Furthermore, the data are limited and insufficient to substantiate the efficacy of antibiotics in preventing endocarditis in patients with high-risk cardiac conditions who undergo dental procedures.6 Failures have occurred even when the infecting microorganism was susceptible to the antibiotic given for prophylaxis. Since bacteremia occurs also during brushing and flossing of teeth, why give prophylaxis just for dental procedures? Moreover, the risks of causing adverse or anaphylactic reactions from antibiotics, as well as contributing to the nationwide antibiotic resistance problem, are issues not to be taken lightly.

Poor compliance with prophylaxis has been documented. Studies by Duval et al7 and others have shown that practitioners adhere to recommended dental prophylaxis programs only about 40% of the time, while only 22% of patients with predisposing cardiac conditions could recall taking their prescribed prophylactic antibiotics before an indicated procedure, as recommended.8

NEW GUIDELINES—2007

To address many of these concerns, the American Heart Association1 released extensively revised guidelines in 2007. They are more pragmatic, narrowly focused for a selected group of patients who have a greater lifetime risk of illness and death from infective endocarditis.

The experts who wrote the guidelines agreed that evidence remains poor about which dental procedures increase the risk of infective endocarditis and the efficacy of antibiotic prophylaxis to prevent its development. They stress the importance of good oral hygiene and prevention of dental disease and argue persuasively that this will have a greater impact on decreasing the lifetime risk of infective endocarditis than will antibiotic prophylaxis.

Prophylaxis is now recommended only for patients with a prosthetic heart valve, a history of infective endocarditis, certain forms of congenital heart disease, and valvulopathy after cardiac transplantation (Table 1), and only before procedures that involve manipulation of gingival tissue or the periapical region of teeth, or perforation of the oral mucosa. Excluded are routine dental cleaning and anesthetic injections through noninfected tissue, dental radiography, placement and adjustment of appliances, shedding of deciduous teeth, and bleeding from trauma to the lips.

Regimens for dental prophylaxis should always be given 30 to 60 minutes before the procedure. Oral amoxicillin remains the drug of choice, and, for patients unable to take oral medications, ampicillin, cefazolin, or ceftriaxone can be used, either intramuscularly or intravenously (Table 2). For penicillin-allergic patients, oral cephalaxin, clindamycin, azithromycin, or clarithromycin is recommended, and, for patients unable to take oral antibiotics, cefazolin, ceftriaxone, or clindamycin, intramuscularly or intravenously.

CONTROVERSY WILL CONTINUE

The new guidelines for dental prophylaxis have been extensively revised and simplified. They are now focused only on patients who have a greater lifetime risk of illness and death from infective endocarditis. But what about patients who had previously been advised to take prophylaxis, such as those with mitral valve prolapse with regurgitation, who will not receive prophylaxis any more?

These guidelines will likely stir emotions, not only for practitioners who have strong desires to practice preventive medicine, but also for patients who have been taking prophylaxis in good faith per previous guidelines. They may feel abandoned. Unfortunately, funding for a prospective randomized clinical trial large enough to prove that antibiotic prophylaxis for dental procedures benefits patients is unlikely. That leaves us with the current recommendations, which are based on scientific evidence that currently exists and on expert opinion.

The intention of the guidelines is laudable. Of course, there will continue to be controversies with the new rules. Nevertheless, we believe they should be followed until there is more persuasive evidence to the contrary.

References
  1. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:17361754.
  2. Hill EE, Herligers P, Claus P, Vanderschueren S, Herregods MC, Peetermans WE. Infective endocarditis: changing epidemiology and predictors of 6-month mortality: a prospective cohort study. Eur Heart J 2007; 28:196203.
  3. Wang A, Athan E, Pappas PA, et al International Collaboration on Endocarditis-Prospective Cohort Study Investigators. Contemporary clinical profile and outcome of prosthetic valve endocarditis. JAMA 2007; 297:13541361.
  4. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997; 277:17941801.
  5. Gendron R, Grenier D, Maheu-Robert LF. The oral cavity as a reservoir of bacterial pathogens for focal infections. Microbes Infect 2000; 2:897906.
  6. Strom BL, Abrutyn E, Berlin JA, et al. Dental and cardiac risk factors for infective endocarditis. A population-based, case-control study. Ann Intern Med 1998; 129:761769.
  7. Duval X, Alla F, Hoen B, et al. Estimated risk of endocarditis in adults with predisposing cardiac conditions undergoing dental procedures with or without antibiotic prophylaxis. Clin Infect Dis 2006; 42:e102e107.
  8. van der Meer JT, van Wijk W, Thompson J, Valkenburg HA, Michel MF. Awareness of need and actual use of prophylaxis: lack of patient compliance in the prevention of bacterial endocarditis. J Antimicrob Chemother 1992; 29:187194.
References
  1. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:17361754.
  2. Hill EE, Herligers P, Claus P, Vanderschueren S, Herregods MC, Peetermans WE. Infective endocarditis: changing epidemiology and predictors of 6-month mortality: a prospective cohort study. Eur Heart J 2007; 28:196203.
  3. Wang A, Athan E, Pappas PA, et al International Collaboration on Endocarditis-Prospective Cohort Study Investigators. Contemporary clinical profile and outcome of prosthetic valve endocarditis. JAMA 2007; 297:13541361.
  4. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997; 277:17941801.
  5. Gendron R, Grenier D, Maheu-Robert LF. The oral cavity as a reservoir of bacterial pathogens for focal infections. Microbes Infect 2000; 2:897906.
  6. Strom BL, Abrutyn E, Berlin JA, et al. Dental and cardiac risk factors for infective endocarditis. A population-based, case-control study. Ann Intern Med 1998; 129:761769.
  7. Duval X, Alla F, Hoen B, et al. Estimated risk of endocarditis in adults with predisposing cardiac conditions undergoing dental procedures with or without antibiotic prophylaxis. Clin Infect Dis 2006; 42:e102e107.
  8. van der Meer JT, van Wijk W, Thompson J, Valkenburg HA, Michel MF. Awareness of need and actual use of prophylaxis: lack of patient compliance in the prevention of bacterial endocarditis. J Antimicrob Chemother 1992; 29:187194.
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Page Number
89-92
Page Number
89-92
Publications
Publications
Topics
Article Type
Display Headline
Infective endocarditis prophylaxis before dental procedures: New guidelines spark controversy
Display Headline
Infective endocarditis prophylaxis before dental procedures: New guidelines spark controversy
Sections
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media

Surprisingly nonbenign imaging

Article Type
Changed
Mon, 04/16/2018 - 14:32
Display Headline
Surprisingly nonbenign imaging

Rarely these days do we hear about a new, nongenetic clinical syndrome, and even more rarely does the news make us rapidly change our practice behavior. But the description of nephrogenic systemic fibrosis and its epidemiologic association with gadolinium exposure in patients with chronic renal disease have led to immediate changes in our choice of imaging studies.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

Article PDF
Author and Disclosure Information

Brian F. Mandell, MD, PhD
Editor in Chief

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Publications
Topics
Page Number
88
Sections
Author and Disclosure Information

Brian F. Mandell, MD, PhD
Editor in Chief

Author and Disclosure Information

Brian F. Mandell, MD, PhD
Editor in Chief

Article PDF
Article PDF
Related Articles

Rarely these days do we hear about a new, nongenetic clinical syndrome, and even more rarely does the news make us rapidly change our practice behavior. But the description of nephrogenic systemic fibrosis and its epidemiologic association with gadolinium exposure in patients with chronic renal disease have led to immediate changes in our choice of imaging studies.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

Rarely these days do we hear about a new, nongenetic clinical syndrome, and even more rarely does the news make us rapidly change our practice behavior. But the description of nephrogenic systemic fibrosis and its epidemiologic association with gadolinium exposure in patients with chronic renal disease have led to immediate changes in our choice of imaging studies.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

Issue
Cleveland Clinic Journal of Medicine - 75(2)
Issue
Cleveland Clinic Journal of Medicine - 75(2)
Page Number
88
Page Number
88
Publications
Publications
Topics
Article Type
Display Headline
Surprisingly nonbenign imaging
Display Headline
Surprisingly nonbenign imaging
Sections
Disallow All Ads
Alternative CME
Use ProPublica
Article PDF Media