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D on a ld L . M iller , M D #{149} R ich a rd C h an g , M D #{149}W illiam T . W ells , R N#{149}arb ara A . D ow jat, R N {149}u th M . M a lin osk y , R N {149}oh n L . D op p m an , M D

In tr a v a sc u la r C o n tra st M e d ia :E ffe ct o f D o se o n R e n a l F u n c tio n

60 7

E ffect o f con tra st m ateria l d o se onc lin ica lly ev id en t ch a n ge in ren a lfu n c tio n w a s stu d ied p ro sp ective lyin 2 00 exam in a tio n s req u irin g in tra -ven ou s or in traar ter ia l a d m in istra -tion of co n trast m a ter ia l. A ll p a -tien ts w ere ad eq u ately h yd rated .B lood urea n itro gen a n d seru m cre -a tin in e w ere m ea su red b efore an dafter th e p roced u re . Io n ic a n d n on -ion ic con tra st a gen ts w ere u sed . T o-ta l d ose o f con trast m a ter ia l ra n gedfrom 3 0 to 5 30 m L (m ean , 2 37 m L ).T h ere w a s n o ten d ency to g ivesm aller d oses to p atien ts w ith p re-ex ist in g ren a l im p airm en t a n d n ore la tion sh ip b e tw een to ta l d ose a n dp atien t ag e . N o con s isten t c lin ica le ffec t o n ren a l fu n ction w as d em o n -stra ted w ith in creasin g d o se, regard -less o f w h eth er io n ic or n on io n icag en ts w ere u sed . In ad eq u ately h y -d ra ted lo w -r isk p atien ts w ith p re-d om in an tly n orm al in it ia l ren a lfu n c tio n an d w ith in th e d ose ran gestu d ied , th ere d oes n ot a p p ea r to b ean y con sistent c lin ica l ch an ge in re -n a l fu n c tio n w ith in creas in g con -trast m ater ia l d o se.

In d ex term s: A ngio gra p h y, complicat ions.96 .448 . A n gio gra phy , co n trast m e dia {149}on -tra s t m ed ia, com para tive stu dies {149}on tras t m e-d ia , to xic ity . K id ne y . fa i lu re , 81 .44

R a d io log y 1 988 ; 167:607-611

I F ro m the D iagn ostic R adio logy D epa rt-m en t, C lin ic al C en ter, N atio nal Insti tu tes ofH ea lth , B ldg 1 0 , R m 1C 66 0, B eth esd a, M D2089 2(D .L .M ., R .C ., W .T .W ., B A D ., R .M .M .,J.L .D .), a nd the D epa rtm ent o f R ad io logy ,G e orgeto w n U niv ers ity M e dica l C en ter, W ash-in gton , D C (D .L.M ., R .C ., J .L .D .). F rom th e 1987R S N A ann ual m ee ting . R e ceived O c tob er 12 ,19 87; rev isio n req ue sted N o ve m b er 10 ; final re-vis ion rec eiv ed Janu ary 12, 1988 ; ac cep ted Ja n-u arv 21 . A d d re ss r ep r in t r eq u es ts to D .L .M .

RS N A , 19 88

A co m m o n teach ing in ang iog ra -p hy is tha t the to ta l dose of con -

tra st m ate r ia l ad m in is tered in one sit-ting shou ld n o t exceed 2 m L /lb (30 0m L for a 15 0-lb pa tien t) o r 4 m L /k g(280 m L for a 70-k g p atien t) (1 ,2 ).M anufactu re rs o f con tra st m ed ia o f-ten sugges t sim ila r m ax im um dosesof con tra st m a ter ia l in the ir pack ag ein se rts. M any endo cr in e loca lizationstud ies requ ire m ore con tras t m ate ri-al th an th e sug gested m ax im um dosefo r an adequa te exam ina tion , and w eh av e rou tin ely ex ceeded these d osesfo r y ears , so m e tim es by a lm o st a fac-to r o f tw o , w itho u t inc iden t.

I t ha s been ou r c lin ica l im pressiontha t, in m o st p atien ts, co n trast m ate -n a can be adm in iste red in do ses con -side rab ly h igh er than those usua llyconside red to be sa fe , w ithou t resu lt-ing in clin ica lly im p ortan t rena l to x ice ffects . T h is be lie f led us to cond uc t ap rosp ec tive study of the re la tio nsh ipbetw e en co ntrast m e diu m do se an dc lin ica l rena l d ysfu nc tio n .

P A T IE N T S A N D M E T H O D SW e p rospec tive ly stud ied 2 30 exa m in a-

t ion s o f inpa tien ts th at re qu ired in tra arte -n a or in trave nou s adm in istra tio n of co n-trast m ate ria l in the sp ecia l p roc edu ressu ite of the N a tion al Ins titu te s of H e alth(N IH ) C lin ical C enter. W e d id not in -dude pa tien ts w ho und erw en t ren a l an -giography or rena l ang iop las ty as part o fa p roc edu re or pat ien ts w ho h ad rece ivedin trave nou s in je ctio ns of con tra s t m ate ri-al els ew here in th e rad io lo gy d epa rtm ent .W e a lso e xclud ed p atie n ts u nde rgo ingsurgery w ith in 36 h ours be fore o r afte rth e ra d io log ic pro ced ure . W ith th ese ex-c ep t ion s, th e se rie s o f exa m inat ion s w asc onse c ut ive .

T he co ntrast m ate ra used w a s eitherio n ic (d ia trizoa te m eg um in e [A ng iov ist2 82 and A ng iov ist 37 0 ; B e r ex , W ay neN J]) o r no nio n ic (io pam id o [I sov ue 3 00;S qu ibb D iag no stic s, N e w B runswic k ,N J]). A ngiov ist 2 82 is a 6 07 so lu tion c on-ta m in g 2 82 m g of iod in e pe r m i i iter,A ng iov ist 370 is a 76 so lu tion c ontain -in g 37 0 m g io d in e pe r m il i iter, an d Iso-

vue 30 0 is a 61 so lu t ion c on tain ing 30 0m g iod ine p er m illil iter . W he n ion ic co n-tra st m a teria l w a s use d , A n giov ist 28 2w as u sed fo r m anua l in jec tions and A n -giovist 3 70 w as use d in th e in jecto r.

C hoice of co n trast m ate ria l fo r a g ive np atien t w as no t rand om . N onion ic co n-tra st m a teria l w a s use d for patie n ts of a nyag e underg o ing p arathy ro id an g iographyan d venous sam pling , pu lm onary an g iog-raph y , sp in al an g io gra phy , a nd per iph er-a an g io gra phy . N onion ic ag en ts w erealso used for c ere bral ang iogra phy afte rthe 9 0 th pa tien t (p rev ious ly ion ic agen tsw e re u sed for bo th h and a nd po w e red in -je ctio ns in p atien ts und erg o in g c ere bra lang iography) .

T h e do se of iod ine ( in g ram s) can becalcu la ted ea sily for those patien ts rec eiv -in g iop am id ol by m u ltip ly in g th e iopa m i-do d ose ( in m il liliters ) by 0 .3 . P atien tsw ho received d ia trizoa te m eg lu m in ew ere g iven th e 60 so lu tion fo r hand in -jec tions a nd the 76 T solu tion for p ow e redin jec tions . M ost of the se patie n ts re ce ive db oth con cen tra tion s du ring the p roc edu reb u t on ly th e to ta l v o lu m e of d iatrizo atem eglum in e w as recorded . T h erefo re , theco rrec t conv ersion facto r fo r de te rm in ingio d ine d ose in th ese pa tien ts v aries be -tw een 0 .282 and 0 .37 b u t is no t know n ex-act ly for ind iv idua l pat ien ts or for thegroup rec eiv ing ion ic a ge nts a s a w ho le.

N o spe cif ic h yd ration o rde rs w e reu sed , exc ep t th at th e p atie n t w as ask ed tocon sum e o nly clea r l iqu ids f rom m id-n ight be fo re the pro ced ure unti l after thep rocedure w as com p leted . O ra l h ydra tionw as a lw a ys perm it ted an d en co urag ed . Ing en era , the N IH n ursing sta ff is w ellaw are of the im portance o f adequa te h y-d rat ion . T o a vo id ex tra at ten tion to h y-d ra tion du ring the s tudy (w ith p oss ib leresu ltan t b ias) , the clin ic ians , w a rd n urs-ing sta ff, and pat ien ts w e re n o t to ld o f th eex is ten ce o f the study . F or the sam e rca-son , inp ut an d ou tput de term in ation s an durin e spe cific gra vity m ea sure m en ts w eren ot don e. C u rio us clin ic ians w ere in -fo rm ed th at p os tp ro ced ure b lo od u rea n i-t rog en (B U N ) an d crea tin ine de term in a-tio ns w e re b eing do ne a s pa rt of a qu alityassu ran ce pro gram . T h is w as possib le b e-c ause the on ly c han ge f rom the reg u la rro u tine of th e sp ecial p ro ced ure s sect ionw as the a ddition o f B U N and serum c re at-m ine dete rm ina tion s 24 ho urs after th e

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T yp es o f P roced u res an d D oses of C on tra st M gter ia l U sed in 2 00 E xam in ation sN o. o f C on tras t M ateria l

T y p e of P roc edu re P ro ced ure s D ose ( m L )A rte ria l pro ced ures

Nonselect ive 23 )A or tog rap h y 23 2 23 6 6

S ele ctiv e a rte riog rap hy (n 1 05 )Bronchial 1 40 0Cerebral 13 17583P a ra th y roid 2 4 3 03 1 24Per ipheral 5 16364S p in al 17 25 6 14 1V isce ral 4 5 2 54 8 4

V en ou s p roce du resV eno us sa m pl ing = 50 )

A d re n a l 4 21 4 6 1P a rath yr oid 8 33435Petrosa sinus 2 8 1 74 86P ortal v eno us 9 397 12 8T h y m i c 1 1 70

V e nou s im ag ing n 22 )U p per-ex trem ity v en ograph y 2 6 0 30P ulm onary a ng iog rap ly 4 27 1 8 6In fe rio r v en a cavograph y

an d in tr ave n o u s d ig ita lsub trac tio n a ngiograph y 1 6 1 53 55

*M ea n s tan d a rd d eviatio n .

T a b le 3C on tra st M ater ia l D o s e in 200 Spec ia l P ro ced ures E xam ina tion s

C o ntrast M ate ria l D ose ( mL )M ea n S D M in im u m M a xim u m

D iatrizo ate m eglu m in e 88 ) 2 39 112 40 520Iopamidol n 112) 236 113 30 530O ve ral (n2 00 ) 2 37 1 13 30 5 30

*S D s tan dar d d eviatio n.

T ab le 1 T a b le 2

60 8 #{149}Radio logy Ju n e 19 88

D iagnoses In 1 53 P atien tsU n d ergo in g S p ec ia l P ro ced u resE x a m i n a t i o n s

D ia gno sis N o . (% )C en tra l n erv ou s system d is-

ease , 1 6 ( 10 .5 )Endoc r ine d iso rders 68 (44 .4 )O th er m alig nan t n e o p l a sm sVascu li t is

4 0 ( 26 .1 )1 7 ( 11 .1 )

Athe rosc le ros is 4 (2 .6 )O th er 8 (5 .2 )

pro ced ure , and th is d id no t requ ire in -fo rm ed consen t. (In gen era l, ven ipun c-tu re does no t requ ire in fo rm ed co nsen t.In ad d itio n , in fo rm ation g ained from th even ipu nc tu re benefited the pa tien t byprov id in g p oten tia l ea rly w arn ing o facu te rena fa ilu re .) A ll pa tien ts gave in -fo rm ed consen t fo r th e rad io log ic p roce-du re itself.

H e igh t and w eig h t m easure m en ts w erem ade b y the w ard nursing s ta ff . W e u sedthe m e asu rem en ts ob tained m os t clo selybefo re the procedure. Fo r p reprocedurede term in ation of B U N and c rea tin ine 1e v-els, w e u sed tho se va lue s ob tain ed m o stclose ly be fore th e pro ce dure . In form ationco llected fo r each pa tien t w ith respec t toth e p rocedure itself inc luded d iagnos is,type o f pro ced ure , co n tra st a gen t u se d , to -ta l c on tras t m ateria l do se (to the n ea rest 5m L ), and a dve rse rea ctio n , if an y . P o st-p ro ced ure B U N an d creatin in e leve lsw e re m easu re d b etw ee n 2 4 an d 72 hou rsa fter the pro cedu re , m os t com m on ly a t 24h ours. A ll d ata w e re re corded o n a datash eet an d tra nsferre d to a co m p ute r fo ranalysis.

A t th e N IH C lin ica l C en ter, th e n orm alrang e fo r B U N leve l is 7 -20 m g/d L (2 .5-7 .1 m m o /L of urea) , an d the norm alrang e fo r se rum crea tin in e leve l is 0 .7-1 .3m g/d L (6 0-1 10 m ol/L ). T h e d ay-to -d ayv ariab i lity in the se m easure m e nts is a p-p rox im ately 2 % fo r va lue s u p to 2 0 m g/d L(7 .1 m m ol/L of urea) for B U N and 2 .0m g/d L (18 0 M m ol/L ) fo r c rea tin ine , in -c rea sin g to ap pro x im ate ly 5 % for B U Nleve ls o f 50 m g/dL (1 7 .9 m m o /L of ure a)a nd c reat in in e leve ls of 5 .0 m g/dL (440M m o l / L ) .

T hirty o f the 2 30 ex am inat ion s w ere ex -c lud ed fro m an aly sis be cau se p atie n the igh t or w e igh t w as u nav aila b le 3) ,preproced ure or pos tp rocedure ren a lfu nct ion d ata w e re un kn ow n (ii 13) ,preproced ure rena l func tio n da ta w ereob ta ined m o re than 10 d ay s befo re theprocedure n 4 ), p o stp roc ed u re ren alfun ctio n w as not m ea sure d betw e en 24and 72 hou rs a fte r th e p rocedure n 7 ,or a d iffe ren t co n tra st a gen t w a s u sed(ti 3) .

T he rem ain ing 2 00 ex am in ations w ereperfo rm ed in 15 3 p atie n ts , w ith m an y u n-d erg o in g m o re tha n on e. P atien ts rang edin a ge from 10 to 79 y ears (m ean , 43 .7ye ars ) an d in w e igh t from 3 1.4 to 1 76 .6 kg(mean , 77 kg ). P a tien t d iag noses are g ive nin T able 1 , a nd the typ es of proce duresan d av erag e do ses of co n trast m ate ria l

u sed fo r e ach a re g iven in T ab le 2 .C alc u lat ion of bo dy surface area w as

p erfo rm ed by m ean s of the s tandard fo r-m ula of D u bois and D ub ois (3 ). D a ta w e rea nalyze d , an d lin ear reg res sion equ atio nsa nd c orrela tion coe ffic ien ts w ere calcu lat-e d w ith stand ard softw a re (S y m p ho ny[version 1 .2]; L otus D eve lop m e nt C o rp .C am bridge , M ass ). S ta tis tica l an aly sis w aspe rfo rm e d by stan da rd m ethod s and tech -n iq ues (4 ).

R E S U L T ST here w ere th ree con trast m ate rial

reactions d uring the 200 exam ina-tio ns. T w o ep isodes (one of nauseaand vo m iting and one of p ru ritu s)occurred w ith d ia trizo ate m eg lu -m ine , and on e (h ypertensio n , con fu -sio n , and transien t b lin dness ) oc-cu rred w ith io pam ido l.

T he overa ll average con trast m ate -ria l dose is g iven in T ab le 3 . T o ev al-ua te the po ss ib le b ias o f reduc tion ofcon trast m ate ria l do se on the bas is o fpatien t a ge or p rep roc edu re re na lfunc tion , to ta l do se w as p lo ttedaga in st pa tien t age (F ig 1) and pre -p rocedure se rum crea tin ine leve l (F ig

2). W ith in the en tire age range of pa-tien ts stud ied , the re w as no c lea rtrend to w ard change in dose leve l fo ran y age gro up . In particu la r, the rew as n o ev id en ce of a decrease in co n-trast m ate rial d ose fo r o lder p atien ts.O f the 3 1 pa tien ts o lde r than 59years, 22 rece ived io pam ido l andn ine rece iv ed d iatrizoa te m eg lu m in e .T h is is no t sign ifican tly d iffe ren tfro m th e d is tr ib u tio n in pa tien tsyo unger than 59 years, 90 of w h omrece ived io pam id o l and 79 o f w homrece ived d ia trizo ate m eg lum ine (x2 .P> .50 ) .

F ig ure 2 dem ons tra tes th at the v as tm ajo rity o f p a tien ts stu d ied had nor-m al ren al fu nc tio n . T h ere w as no ev i-dence o f a tendency to adm in is terless co n trast m ate rial o r a n on ion icagen t to those few pa tien ts w ithc lear ly d ecreased rena l func tion be-fo re th e pro ced ure . O f the 15 pa tien tswith a p reprocedure c rea tin in e leve lg rea te r than 1 .5 m g/d L (13 0 m o l/L ),sev en rece ived iopam ido l an d e igh treceiv ed d ia trizoa te m eg lum in e.E ven in th is sm all su bse t o f pa tien ts ,the re w as no correla tion b e tw een

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3/5

+ O K T K 2 O U E , AS GPAMIOOL

1 2 3P RK -A RT ER I0 00 AG C 00 41 1N IP A( ( ,+ q/ dl (

05016120000S 0*450001

A*+

+ 05010120000S 0*461001

V o lum e 16 7 N u m b er 3 Radio logy {149}09

S

1.

S0 0

500

400

300

200

too

0 2 0 4 0 0 0AG O

000

500I0 0

2.

300

200

100

oA *

+ D 01012001E0*450001

F i g u res 1 , 2 . (1 ) P lot of to ta l c on tra st m ater ia l d ose a s a fu n ction of a ge. L in ea r re gre ssionl ine y = a + bx is sh ow n a nd ha s the fo llo w in g pa ram ete rs: a 1 78 .5 11 1 .3 (stand ard er -ro r ) , b = 1 .33 8 0.529 ; r = .176 , P > .10 . T here w as n o e vid en ce of a te nde ncy to use low erd oses of con tra st m a teria l fo r o lder adu lts . (2 ) P lo t of to ta l c on tras t m ateria l do se a s a func -t ion o f in itia l c rea tin ine lev el. M ost pat ien ts had an in itia l s eru m cre atin in e leve l o f 1 .5 m g/dL (130 m ol/L ) or le ss. L ine ar reg res sio n line ha s the fo llow in g param eters: a 233 .9 113 .1 , b = 2 .93 7 19 .02 ; r .00 , P > .50 . T here w a s n o e vid enc e o f a te nd enc y to g ive le ssc on tras t m ateria l to pa tie n ts w ith e leva ted in i tia l serum c rea tin ine lev els .

30

20

10

-10

a.

-20

-302 00 4 00

T OT Al. C ON TR AS T M AT OR IA L D OS S ( I )800

2

I oe, 0.6

0.2 0 -0.2S -0.4 -0.6 -0.6

-1,2

b.2 00 4 00

T O T K . C O N T R A S T 0 01 16 50 . D OS E ( 45 )

F ig u re 3 . P lo ts i llu s tra te e ffe ct of co n tr ast m a ter ia d ose o n r en a l fu n c tio n , m easu r ed b ychanges in B U N (a) and serum crea tin in e (b ) lev e ls . P reo pera tive leve l is sub trac ted fro mp os top era tive le vel. R e su l tan t va lue is p osi tive for n et inc rea ses in B U N a nd creat in in e an dn eg ative fo r n et d ecr eases in th e se tests. R e gr ession lin e is p lo tte d on eac h gr ap h : for (a ), a-2 .2 6 4 .314 , b 0 .0 0 0 .0 02 ; r .00 a nd fo r (b ), a -0 .0 3 0 .195 , b 0 .00 0 .00 ; r .00 .N ote th at there is n o tren d tow ard ren al dy sfu nct ion w ith h ig her d ose s o f co n trast m ate ria l .Separa te reg ress ion lines and co rre lation co effic ien ts fo r d ia trizoa te m eg lum ine and io pam i-d o are n o t sh ow n , b u t the y w ere sim ilar to the va lue s ob taine d for th e ove rall ser ies , w h ichind icates th ere w e re n o de m o nstrab le d iffe ren ces b etw ee n the tw o co ntrast a ge n ts in th isset t ing .

con trast m ater ia l dose an d ch an ge increatin ine leve l, regard less o f w he th -e r do se w as exp ressed in m illilite rs,m illilite rs per k ilo g ram , or m illilite rsp er squ are m ete r r = .094 , . 104 , and. 03 1, r es pe ct iv el y) .

T o eva lua te the effec t o f con tras tm ate ria l do se on rena l func tion ,c h a n g e in re n al fu n c tio n w a s p lo ttedaga in st co n trast m ater ia l dose (F ig 3).C hange in rena l func tion w as m ea-su red by sub trac ting the p reproce-d ure va lue fo r B U N or crea tin in ef rom the pos tp rocedure va lue . A pos-itive resu lt rep resen ts an increm en ta ld ecrease in rena l func tion , w hereas anega tive resu lt rep resen ts an incre -m en ta l im prov em en t in rena l func-tion . N o gross change in ren al fu nc-tion w as iden tif ied w ith inc rease ind ose . T o co rrec t fo r v ary ing pa tien tw eigh t and hab itus, sim ilar g raphs

w ere cons tru c ted , bu t w ith con tras tm ater ia l dose expressed as a func tio nof pa tien t w eig h t (F ig 4) o r b ody sur-face area (F ig 5). A g a in , n o ev idenceof de te rio ration of rena l fu nc tio nw ith in creas ing con tras t m ate ria ldo se w as iden tified . N o corre la tionbe tw een th e dose of con tras t m ate ria land ch an ge in rena l fun ction w asseen .

A ltho ugh no t show n, reg ress io nlines and corre la tio n coeffic ien tsw ere also ca lcu la ted fo r iopam ido land d iatrizoa te m eg lum ine separa te -ly fo r each grap h . W ith respec t tochang e in crea tin ine lev el, th e s lopeof all reg ress ion lines w as 0 .00 , asw as the co rre lation coeffic ien t. W ithresp ect to change in B U N leve l, th eslo pes o f reg ress io n lines w ere 0 .00to -0 .3 7 fo r d ia trizoa te m eg lum ineand 0 .0 05-0 .247 fo r iopam ido l. C orre -

la tion coeffic ien ts w ere be tw een .13 0an d .210 fo r d ia trizo ate m eg lum inean d .105 an d .1 64 fo r io pam ido l.T h ere w as there fo re n o ev idence of acorrela tion be tw een the dose of d ia -trizoa te m eg lu m ine or tha t o f io pa-m ido l and gross change in rena lfunction.

F ina lly , w e ev alua ted the effec t o frepea ted adm in is tration of con tras tm ate ria l by eva lua tin g ren al func tionin ten p atien ts w ho un derw en t tw ospec ia l p ro cedu res, each in vo lv ingthe ad m in istra tio n of a t leas t 200 m Lof con trast m ate rial. In each p a tien t,the tw o p rocedures w ere separa tedb y a rest d ay . T he com bined con trastm ate ria l dose fo r the tw o pro cedu resav erag ed 6 39 m L (range , 43 0-925m L ) adm in iste red w ith in 48 hou rs. Inthese pa tien ts, the re w as no ev idenceof a trend tow ard de te rio ra tion of re -na l func tion (F ig 6).

D I S C U S S I O NT here is no q uestion tha t the in tra -

a rte ria l o r in travenous adm in istra -tion of con tras t m ate ria l can im pa irrena l fu nc tion . V ario us risk fac to rsh av e b een im p lica ted a s p red isp os in gto rena l dam age , in c lu d ing dehyd ra -

_600 tion , d iabe tes m ellitu s, m ultip le m y -e lom a, p reex is ting rena l d isease , age ,a n d th e typ e of s tu d y (5-9). S om es tud ies have sug gested th at the vo l-um e of con tras t m ate ria l adm in is -te red is a lso a fac to r in de te rm in ingth e l ik e lih ood o f re n a l d ys fu n ction(8 ,9 ) .

In th is stu dy w e exam ined gro sschang es in rena l fu nc tion in a co n-secu tiv e se ries o f rela tive ly lo w -riskpa tien ts. O n ly 7 .5% (15 of 2 00) h ad anin itia l se ru m creatin ine leve l g rea terthan 1 .5 m g /d L (13 0 M m ol/L ). Severecard iac d isease w as u nusua l. A l-thoug h o ur pa tien ts a re atyp ica l w ithresp ec t to th e re la tiv e frequency ofvariou s ca tegories o f d isease (T ab le1) , w e believ e they represen t a rea -sonab le sam ple o f o therw ise re la tive -ly low -risk ind iv idua ls w ho un dergoang iography .

W e w ere u nab le to d em onstra te ev-idence o f an y gro ss chang e in rena lfu nct ion re su lt ing from in cre asingcon tras t m ate ria l d ose (F igs 3 -5 ). F ur-the rm ore , th ere w as no d iffe rencebe tw e en dia triz oate m eg lum in e an diopam ido l in te rm s of the ir effec t onrena l fun ction . T he ab sence of g rossrena l d e te rio ra tion ex tend ed to thesubse t o f 15 pa tien ts w ith in itia l c re -a tin ine lev els g rea ter than 1 .5 m g/dL(130 m ol/L ) , as w ell as the subse t o ften pa tien ts w ho rece iv ed 4 30-92 5m L of con trast m ater ia l du ring a pen-

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a . b .F igu re 4 . P lots il lu s tra te ef fec t of co n tr ast m ate ria l d ose on r en al fu n c tio n c or rec ted fo r d if-fe rences in pa tien t w eig ht. D ose of con tras t m a teria l is e xpressed as a func tion o f pa tien tw eig h t (m illi lite rs per k ilogram ) an d plo tte d a gainst c han ge s in B U N (a) and c rea tin ine (b )leve ls, a long w ith the reg ress ion lin e, as in F ig ure 1 . R esu lts a re sim ila r. F or (a ), a -2 .2 5 4 .314 , b = -0 .0 2 0 .182 ; r .0 0 . F or (b ), a -0 .02 0 .19 5 , b 0 .00 0 .008 ; r .00 . 0010120001

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b.F ig u re 5 . P lo ts illu str ate e ffe ct o f c on tra st m ateria l d ose o n re n al fu n ction co rre cte d fo rvary ing pat ien t hab itu s. D ose o f co n trast m ate ria l is e xpressed a s a fu nc tion o f b od y sur faceare a (m illili ters p er squa re m eter) an d plo tte d a gainst c han ge s in B U N (a) and creat in in e (b )leve ls, a s in F igure 1 , a lon g w ith th e reg res sio n lin e, w ith s im ilar re su l ts. F o r (a) , a -1 .9 2 4 .310 , b = 0 .0 0 0 .00 4; r .044 . F or (b ), a -0 .0 2 0 .1 95 , b 0 .00 0 .00 ; r .00 .

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a . b .F igu r e 6 . G r ap h s of ser ia l m ea su rem en ts of B U N (a) an d seru m cre atin in e (b ) le vels in tenpa tien ts u nd erg o in g tw o sp ecial p roc edu res 2 da ys a par t. P roc edu res w e re pe rform e d o nd ays 1 a n d 3 . R ena func tio n w a s m ea sured on da ys 0 , 2 , and 4 . E a ch pro ced ure inv o lv ed thea dm in is tra tion of at leas t 2 00 m L o f c ontras t m a teria l; the av era ge doses are sh ow n. T he rew as no ten den cy tow ard re nal d ysfu nc tion d uring th e per iod show n.

61 0 . Radio logy J u n e 1 988

separa te p rocedures.T h is s tu dy m igh t b e critic ized on

the grou nds th at po stp ro cedu re B U Nan d cn ea tin ine leve ls w ere usua llym easu red 24 hou rs af te r th e proce-dune and no t a t 48 hours o r longer, ashas been d one in m o st o the r stud ies(8 -11). D ram atic inc reases in cn ea ti-n ine leve l m ay no t occur u n til 48hou rs a fte r the procedu re , and w em ay h av e m issed cases o f ren a l fa il-u re fo r th is reason . H o w ever, O ldere t a l (12 ) show ed tha t con tras t m ed i-um -ind uced rena l fa ilu re resu lted indem on strab le inc reases in se rum cn e-a tin ine leve l by 24 hours in seven ofthe ir n in e p atien ts. N one of o ur pa-tien ts h ad sim ila r inc reases in crea ti-n ine leve l. If w e had used a m oreconserva tiv e c rite rion (ie , cons id e r-ing rena l fa ilu re to h av e o ccurred ifthe re w as a 50% increase in c rea ti-n ine leve l), on ly on e of our pa tien tsw ou ld have been ju dged as hav ingrena l d ysfu nc tio n (th is pa tien t ne-ce ived 105 m L of iop am id o l and h ada se rum crea tin in e lev el tha t in -c reased from 1 .0 to 1 .5 m g/dL [90 to13 0 im ol/L ]) . N o ne of our pa tien tshad c lin ica lly app aren t acu te rena lfailu re , w h ile five of sev en pa tien tsin th e se ries o f O lder e t a had o ligu -n a . Fur th erm ore , se ria l m easure -m en ts o f B U N an d creatin ine w ereava ilab le fo r the ten pa tien ts in ourse ries w ho und erw en t tw o h igh-do sestud ies 48 ho urs apart, and these p a-tien ts had no labo rato ry ev idence o frena l de ter io ra tion (F ig 6). F ina lly , 47o f th e exam ina tio ns reported here inw ere su bsequ en t p rocedures per-fo rm ed in pa tien ts already en te red inthe stud y . W e rev iew ed the chartsand ava ilab le labo ra to ry da ta fo rthese pa tien ts a t the tim e of the irsubsequen t s tudy . N one had c lin ica lo r laborato ry ev idence of rena l fa il-u re assoc ia ted w ith the ir in itial ex -aminat ions.

C an ou r ex perien ce be g en eralizedto oth er p atien t p op u la tion s? T he pa-tien t p opu la tio n in th is se ries w asrepresen tative o f N IH ex perien ce b u tw as o therw ise a ty p ical. M os t (92 .59k)o f the p a tien ts in th is s tu dy had nor-m al rena l fun c tion , none h ad m ulti-p ie m yelom a, and n o m ore th an fivehad d iabe tes. T h e preva lence o f h eartd isease an d a thero sc le rosis w as a lsoex tremely low in th is po pu la tio n (T a-b le 1 ) com pared w ith tha t in th e typ i-ca l pop u la tion seen in m ost specia lp ro cedu res laborato r ies .

T he prev alence of re la tive ly un-usu al d iso rd ers, espec ia lly endo cr in ed iso rders , w as m u ch h igher in th isse ries than w ould be expec ted in a

s tan dard ang iog raphy p rac tice . T h ishas a d irec t e ffec t on the resu lts fo rtw o reason s. F irst, these pa tien ts ten dto be re la tiv e ly h ealthy excep t fo rth e ir endocrine prob lem . it has beensh ow n th at d iabe tes (5 ,6 ,9 ), hea rt d is -ease (8 ), and underly ing rena l in su f-ficiency (5 -9 ) can p red ispose to th edeve lopm ent o f rena l fa ilu re a fte rcon tra st m ateria l a dm in istra tion , al -tho ugh they d o n o t invariab ly d o so(11). C au tio n is appropria te in the ex -tensio n of our resu lts to pa tien ts w ith

these d iso rders . S eco nd , pa tien tsw ith endocrine d iso rd ers co nstitu tedthe m ajo rity o f th ose w ho rece ivedthe h igh es t do ses o f con tras t m ate ri-a l. O f the 13 ex am ina tions in th is Se-n ies in w hich 4 50 m L or m o re of con-trast m ate ria l w as adm in is te red , allw ere p arathy ro id arte riog ram s, sp i-na l a rten io gram s, o r porta l veno ussam p ling . A ll ten p atien ts w ho un -derw en t tw o exam ina tion s 48 hoursapart (F ig 6) had hy perpara thyro id -ism , Z o lling er -E llison syndro m e, o r a

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5/5V olu m e 167 N um b er 3 R ad io lo gy #{149} 11

sp in a l a rte riovenou s m alfo rm ation .T hose p atien ts w ho rece ived th e

h ighes t doses o f con trast m ate ria ltended to have undergo ne re la tive lylen g thy , tim e-consum ing procedures,so th at the to ta l d ose of con tras t m a-teria l w as ad m in iste red d uring a pe-nod o f 1 -2 .5 hours . A dm in is trationof con tras t m ate ria l do ses th is h ig hdur in g a period of a few m inu tesm igh t n o t be to lerated as w ell. H ow -ever, H aym an e t a l (1 3) show ed th ath igh doses o f con tras t m ate ria l (8 0 gof iod ine , eq u iva len t to 2 65 m L of a60% con tras t m ate ria l such as Isovue300) can b e g iv en o ver 10 m inu tesw ith no in crease in the ra te o f rena ldysfunc tion co m pared w ith the ra teresu lting from a sm aller d ose o f 40 gof iod ine g iven in th e sam e fash io n .Fu rth e rm ore , R u b in e t a l (1 4) show edin a rabb it m ode l tha t ev en w ith in -term itten t (every 10 m in u tes ) in jec -tio n of a liq uo ts o f d iatrizoa te m eg lu -m ine /sod ium , se rum iod ine con cen -tration and o sm ola lity inc reased w itheach success ive in jection . T h is sug -ges ts th a t the period during w hichcon tras t m ate rial is adm in iste red m ayno t b e of m ajo r sign if icance .

A fina l fac to r is the em p hasis o nh ydra tion in our pa tien ts. A lthou ghw e canno t p rove tha t a ll p atien tsw ere w ell hyd ra ted , c lin ic ians a t theN IH C lin ica l C en ter a re w ell aw areof th e do ses o f con tras t m ate rial w ecom m only use . In consequence , som epa tien ts , pa rticu la rly those w ith hy-perpara thyro id ism and Z olling er -E l-liso n syn drom e, rece ived in trave-n ous hyd ra tio n in add itio n to ora lh ydra tion . T h e decreases in B U N 1ev-e l n o ted a t h igh con trast m ate ria ld oses (F igs 3 -5 ) m ay b e accoun ted fo rb y th e overhy dra tio n and d iu res iscau sed by th is p rac tice . It m us t ben o ted , h ow ev er , th at hydra tion is no ta panacea , and con trast m ate ria l-in -duced rena l fa ilu re can occur desp itev igoro us hydra tion (9 ).

T h ere is bo th theore tica l (1 5) an dexp erim en ta l (16 ) ev idence to sug-

g est th at iopam ido l shou ld be lessn ephro tox ic than is d iatrizoa te m e-g lu m ine . H ow ever, ou r s tudyshow ed ne ithe r ag en t to be p articu -la rly tox ic c lin ica lly , and w e iden ti-f ied no rea l d iffe rence be tw eenthem . T h is is in accordance w ith thes tudy o f G ale et a l (17) in h um ans inw hich a sens itive en zym e m arker o fren al in ju ry w as u sed and n o d iffer -en ce in neph ro tox ic ity w as foundam ong io pam id o l, io tha lam ate , an dd ia t r izoa te .

C on trast m ate ria l tox ic ity is no tlim ited to ren a l dysfun ction , o fco urse . T ox ic ity to the cen tra l ne r-v ous sy stem , h ear t, an d lun gs m usta lso be cons id ered w hen h igh do seso f these agen ts a re used . A lthou ghw e encoun te red on ly th ree ins tan ceso f con trast m ate ria l reac tion o r tox ic -ity , none o f w hich app eared to bed ose re la ted , these fac to rs m ust a lsob e con sidered befo re pro ceed ingw ith th e adm in istra tion o f la rg ed oses o f con trast m ate ria l.

W e co nc lu de th a t in pa tien ts w ithre la tiv ely norm al ren al an d card iacfu nc tion and w itho u t d iab etes m elli-tu s o r m ultip le m y elo m a, very larged oses o f con trast m ate ria l app ear tob e to le ra ted as w ell as sm aller doses,if adequa te p atien t hydra tion is used .In ou r p atien ts the re w as no id en tifi-ab le trend tow ard d ete rio ra tion of re -na l func tion w ith inc reas in g con trastm ate rial do se over the do se ranges tud ied . N o d iffe rence w as ev iden tb e tw een d ia trizoa te m eg lum ine an diopam ido l in th is stu dy . T hese resu ltsm ay no t app ly to h igh-risk p atien ts,e spec ially those w ith preex isting re -na l im p airm en t. U

R ef eren ces1 . R e ute r S R . R e dm an H C . G a stro in test ina l

ang iog rap hy . 2d ed . P h ilade lph ia: S au n-ders, 1 977 ; 17 .

2 . A b ram s H L . T h e o paq ue m ed ia: p hy sio -lo g ic effects an d sys tem ic reac tion s. In :A bram s H L , e d . A b ra m s ang iogra phy: va s-c u lar an d in terv en tiona l rad io lo gy . 3d ed .B oston : L ittle , B row n, 1 983 ; 20 .

3 . D u bo is D , D ubo is E F . A fo rm u la to est i-m ate the ap pro x im ate sur fac e are a ifh eig h t a nd w e igh t be k now n. A rc h In ternM ed 1 9 1 6 ; 1 7 :8 6 3 -8 7 1 .

4 . S w insc ow T D V . S tat istics at sq ua re one .L on do n: B r itish M ed ica l A sso cia tion ,1 9 8 0 .

5 . W ein rau ch L A , H ea ly R W , L e lan d O S J r,e t a . C oro na ry ang iog rap hy and acu terena l fa ilu re in d iab etic azo tem ic ne-p hropa thy . A nn In tern M ed 19 77; 86 :56-59 .

6 . A lex and er R D . B erk es S L , A bu elo JG .C o ntrast m edia-in du ced oligu ric re nalfa ilu re . A rch In tern M ed 1 978 ; 1 38 :38 1-3 8 4 .

7 . C oc h ra n S T . W on g W S , R o e D J. P red ict -ing an gio gra ph y-in du ced ac u te ren alfun ctio n im pairm e nt: c l in ic al risk m ode l.A JR 1 98 3; 1 41 :1 02 7- 10 33 .

8 . M artin -P are dero V . D ix on S M , B a ke r JD ,et a l. R isk o f rena l fa ilu re a fter m a jor an-g io grap hy . A rch S u rg 19 83 ; 1 18:141 7-1 4 2 0 .

9 . C om es A S , B ak er JD . M ar tin -P a red ero V .e t a l. A cute re nal d ysfunc tio n af ter m ajora rt er io gr ap hy . A JR 1 98 5; 1 45 :1 24 9- 12 53 .

10 . C ram er B C , P arfrey P S , H utc h in son T A , e ta . R e na fu nc tion fo llo w ing in fus ion ofrad io log ic co n tra st m ateria l: a p rospec tiv ec on tro l led study . A rch In te rn M ed 19 85;145:87-89 .

1 1 . C rux C , H r icak H , S am ho uri F , S m ith R F ,E yler W R , L av in N W . C on tras t m ed ia fo ran g io gra phy : effect on re nal fu nc tion . R a-d io og y 19 86 ; 1 58 :10 9-1 12 .

12 . O lde r R A , K o rob kin M , C leev e D M ,S ch aaf R , T h om pso n W . C ontrast-in -d uc ed ren al fa ilu re : p ers iste n t ne phro-g ra m as clu e to ear ly d ete ction . A JR 1 98 0;134:339-342 .

13 . H a ym an L A , E van s R A , F a hr L M , H inckV C . R en al con se q u e n c es o f rap id h ighd ose c ontrast C T . A JR 1 980 ; 1 34:553 -55 5 .

14 . R u bin D I, K id o D K , M o rris T W , F ische rH W . E ffect o f m u ltip le in trave nou s in je c-tio ns o f d ia trizoa te o n io dine con ce ntra-tio ns a nd o sm ola ity : a n e xpe rim en tals tud y in ra bbits . Inv es t R a dio 198 7; 2 2:223-226.

15 . D a w son P . C on tras t age n t ne ph ro to x i-c ity : an a ppraisa l. B r J R ad io l 1 98 5; 58 :12 1-124 .

16 . L un d C , R ysa vy J, S alo m o no w itz E , et a l.N ep hro tox icity of co n trast m edia as ses sedb y o cc lus ion arterio graph y. R ad io log y1 9 84 ; 1 5 2: 6 1 5- 6 19 .

17 . G a le M E , R obb ins A H , H a m b urg er R J , W i-d ric h W C . R ena l tox icity o f con tra sta ge n ts: iopa m idol , io tha lam ate , a nd dia tri-z oate . A JR 19 84 ; 1 42:33 3-3 35 .