1988 almanya

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‘Depa rtment of Rad io lo gy , M assachu se tts G enera l H osp ita l, H a rv a rd M ed ica l C en te r , Bo s to n , M A 0 21 14 . Addres s r ep ri nt r e q ue st s t o J . T . Ferrucc i.

1231

A JR 15 0 :12 31 -12 33 , J un e 1 98 8 03 61 -80 3X /8 8 /i 50 6 -1 231 © A m eric an R oe ntg en Ra y Soc ie t y

G a lls tone ESW L -The F irs t 175 Pa tien ts

Joseph T . F e rrucc i1

Perspect i ve

Any doub t tha t the success o f ex tra co rporea l shock -w ave

litho tr ip sy (ESW L) fo r k idney s tones cou ld be trans fe rred to

ga lls tones has been d ispe lled by the landm a rk repo rt o f

S ackm ann e t a l. [1 ] from W est G e rm any, w h ich appea red in

th e N ew E ng land Jou rna l o f M ed ic ine in Feb ruary 1 988 . In a

m a jo r expans ion o f the ir in itia l repo rt o f n ine pa tien ts [2 ],

w h ich appea red 2 yea rs ea r lie r in the sam e jou rna l, the

p resen t s tudy docum en ts success fu l in itia l fragm en ta tion o f

ga lls tones in 1 74 o f 1 75 patien ts , w ith neg lig ib le com p lica -

t ions .

T he au tho rs , m os t o f w hom a re gas troen te ro log is ts and

eng inee rs a t D o rn ie r (M un ich -G e rm e ring , W . G e rm any ),

trea ted a ll the ir pa tien ts by us ing a m od ified Do rn ie r HM 3

w a te r- tank k idney litho tr ip to r spec ifica lly fitted w ith a rea l-

tim e sonog raph ic s canne r fo r lo ca liza tion . H oweve r, s in ce

Sep tem be r o f 1 987 , an equa l num be r o f pa tien ts have been

trea ted w ith s im ila r success on an im proved , second -gener-

a tion non -w a te r ba th un it, the M PL -9000 .

The find ings o f S ackm ann e t a l. [1 ] cam e as no su rp r is e to

a ffic ionados o f b ilia ry litho trip sy , m any o f whom had v is ited

M un ich wh ile the s tudy was in p rog ress . H ow eve r, w ith the

pub lica tion o f th is s tudy as a lead a rtic le in the New Eng land

Jou rna l o f M ed ic ine , the resu lts assum e imm ed ia te and w ide -

sp read s ign ific ance . F o r the one in 1 0 adu lts w ho w ill deve lop

ga lls tones , an appea ling new the rapeu tic op tion is now im -

m inen t; a new segm en t o f the m ed ica l equ ipm en t indus try

has been ene rg ized ; and a decade -o ld bu t som ew ha t igno red

m ed ica l d isc ip line , chem o ly tic the rapy o f ga lls tones , has been

r e deemed . A ll o f the above g ive s trong im pe tus to the F ood

and D rug Adm in is tra tion -m on ito red , m u lticen te r c lin ic a l tria ls

be ing in itia ted by D o rn ie r and seve ra l o the r m anu fac tu re rs

na tionw ide and p rom ise to m a rk 1988 as a landm a rk yea r in

the trea tm en t o f ga lls tone d isease .

How va lid are the resu lts o f the M un ich s tudy? W ilF they be

subs tan tia ted by s tud ie s in the U n ited S ta tes? W ha t te chn ica l

and c lin ica l issues a re no t answ e red? W ha t a re the im p lica -

tio ns fo r r ad io lo gis ts ?

U n ique c lin ic a l de ta ils em e rg ing from the s tudy dese rve

em phas is . S tric t e lig ib ility c r ite r ia a llow ed on ly 28% o f re fe rred

pa tien ts to be accep ted fo r trea tm en t. T hese inc luded requ ire -

m en ts tha t pa tien ts have sym p tom s , have th ree o r fewe r

ga lls tones , have s tones no g rea te r than 30 mm , have no

ca lc ifica tion on a p la in abdom ina l rad iograph , have a func tion -

ing o ra l cho le cys tog ram , and have no o the r m ed ica l con tra in -

d ic a tions such as acu te b ilia ry obs tru c tion , s igns o f cho le cys-

titis , p regnancy , o r arrh y thm ia . O f the 1 75 patien ts se le c ted

fo r ESW L , 1 45 had a so lita ry ga lls tone w ith a m ean d iam e te r

o f 1 9 mm ; the rem a in ing 30 pa tien ts had tw o o r th ree ca lcu li.

P a tien ts w e re trea ted in the p rone pos ition w h ile pa rtly im -

m e rsed in the w a te r ba th w ith the shock w aves en te r ing v ia

the ven tra l s ubcos ta l a rea . E CG tr igge r ing was used , and a

to ta l o f 430 to a m ax im um o f 1600 shock d ischa rges we re

de live red in a range o f 1 3 -1 65 mm . F ragm en ta tion was

m on ito red sonog raph ica lly un til lo ss o f the echogen ic fo cus

and acous tic shadow occu rred . T he lim it o f 1 600 shocks was

chosen on the bas is o f pub lis hed b ioe ffe c ts da ta in an im a l

expe r imen ts .

G ene ra l anes the tic was used in the firs t 54 pa tien ts , bu t

m o re than ha lf (56% ) o f subsequen t pa tien ts we re g iven on ly

IV op ia te s , w h ile the res t w e re g iven ep idu ra l anes the tic

(22% ), gene ra l anes the tic (21 % ), o r no anesthe tic a t a ll (1 % ).

E ach pa tien t re ce ived ad juvan t o ra l b ile ac id the rapy to d is -

so lve res idua l fragm en ts . The m ed ica tion reg im en cons is ted

o f a com b ina tion o f chenodeoxycho lic ac id and u rsodeoxy-

cho lic ac id adm in is te red in a s ing le dose o f 7 .5 m g each a t

bed t ime . This m ed ica tion was s ta rted app rox im a te ly 2 w eeks

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ESWL +

O ra l B ile

Ac ids

10 0

75

504.

‘I

O ra l B ile

Ac ids

25

03 6 9 1 2 1 5 1 8 2 1 24

Mon ths

1232 FERRUCC I A JR :1 50 , J un e 1988

F ig . i . - ldealized p lo t of enhance d e ffec t o f m ech an ica l E SW L frog -

menta t t on vs ora l b ile a c id th erap y a lo ne .

be fo re the rapy and con tinued fo r 3 m on ths afte r the com p le te

d isappea rance o f s tones .

O n the firs t pos tope ra tive day , sonog raph ic fo llow -up re -

vea led m u ltip le sm a ll fragm en ts 2 -4 mm in s ize in a ll bu t tw o

pa tien ts . In m ost pa tien ts (1 3 7 ), the fragm ents ave raged 2

mm in d iam e te r and appea red sonog raph ica lly iden tic a l to

sand or s ludge . La rge r fragm en ts up to 4 mm w ere m o reo ften seen in pa tien ts w ith tw o o r th ree s tones , and ove ra ll

n ine pa tien ts requ ired add itiona l trea tm en t because o f the

la rge r re s idua l fragm en ts .

The p rin c ipa l c r ite rion o f success w as sonog raph ic c lea r-

ance o f fragm en ts from the ga llb ladde r on fo llow -up im ag ing .

O ve ra ll, the ra te o f c lea rance from the ga llb ladde r w as 30%

o f a ll pa tien ts a t 2 m on ths a fte r litho trip s y ; c lea rance in -

c reased w ith tim e to 48% a t 2 -4 m on ths , 63% a t 4 -8 m on ths ,

and 91 % a t 1 2 - i 8 m on ths . T he 88 pa tien ts (50% o f the

se r ie s ) w ith so lita ry s tones up to 20 mm gave even be tte r

re su lts , w ith co rre spond ing ga llb ladde r c lea rance ra tes o f

45% , 69% , 78% , and 95% , respec tive ly . H oweve r, in the

sm a lle r g roups o f pa tien ts w ith s tones 20 -30 mm , and in

those w ith tw o o r three s tones , re su lts w e re le s s favo rab le .F ragm en t s izes w ere la rge r (m ean , 4 .6 mm ), the ra te o f

ga llb ladde r c lea rance was s lowe r, and the pe rcen tage o f

u ltim a te successes tended to p la teau a t 75% -80% .

W he ther it w as spon taneous fragm en t passage o r b ile ac id

d isso lu tion tha t w as respons ib le fo r fragm ent c lea rance can -

no t be asce rta ined . N eve rthe le ss , one o r m o re ep isodes o f

b ilia ry co lic w e re repo rted by 35% o f a ll pa tien ts , w ith the

num be r o f ep isodes g radua lly decreas ing w ith tim e . R em a rk -

ab ly , o the r com p lica tions we re neg lig ib le . M ild pancrea titis

w as no ted in tw o pa tien ts , one a t 6 m on ths a fte r trea tm en t.

O n ly tw o pa tien ts requ ired ERCP fo r re s idua l fragm en ts in

the comm on b ile duc t, and on ly one requ ired endoscop ic

sph in c te ro tom y . B o th o f these pa tien ts w e re in the firs t g roup

o f n ine in the in itia l pub lished repo rt [2 ]. M ino r cu taneouspe tech ia l hem o rrhages we re obse rved in 1 4% o f the pa tien ts ,

w h ile trans ien t hem a tu r ia occu rred in 3% . The pe tech iae w e re

though t to be caused by the cav ita tion e ffe c ts o f the shock

w aves a t the a ir-sk in in te rfa ce .

A re these resu lts too good to be accep ted a t fa ce va lue?

Some su rgeons m igh t hope so . S e lec tion o f pa tien ts ce rta in ly

is a fac to r. F o r exam p le , it is h igh ly un lik e ly tha t the m ost

fa vo rab le cand ida te s itua tion , a so lita ry s tone le ss than 20

mm , w ill o ccu r in 50% o f pa tien ts a t m ost ESW L cen te rs .

D ata from a recen t sonog raph ic su rvey o f ga lls tone m orpho l-

ogy in a la rge se r ie s o f pa tien ts in Ita ly sugges ts tha t th is

p robab ly occu rs , a t m os t, in on ly 1 5% -20% o f pa tien ts [3 ].

T he 28% pa tien t accep tance ra te is o f fu rthe r no te , w ith m ost

pa tien ts be ing exc luded because o f m u ltip le s tones (44% ),because the ga llb ladde r w as no t seen on o ra l cho le c ys tog -

raphy (1 7 % ), o r because o f ca lc ifica tion (1 5% ). D a ta from the

Ita lian s tudy and p re lim ina ry da ta ga the red in ou r depa rtm en t

sugges t an ove ra ll cu rren t ESW L e lig ib ility ra te o f on ly 25% .

O bv ious ly , a s w ith rena l ESW L , c rite ria a re lik e ly to be m o re

libera l in the fu tu re . M o reove r, p ro to co ls fo r repo rting p roce -

du re com p lica tions from Eu ropean inves tiga to rs do no t a l-

w ays con fo rm to the trad itions fo llow ed in Am e rican cen te rs .

A lso , in th is in s tance , it is poss ib le tha t pa tien ts m ay have

com e to M un ich from o the r c itie s and tha t m ino r o r subacu te

com p lica tions days o r w eeks a fte r ESW L may no t have been

p rec ise ly repo rted . F ina lly , the requ irem en t fo r long -te rm

chem o ly tic m ed ica tion adds a s ign ifican t cos t in c rem en t.

T he less favo rab le resu lts w ith la rge and m u ltip le s tones

(g rea te r ove ra ll s tone m ass) w e re be lie ved re la ted to the

d ifficu lty in sonog raph ic v is ua liz a tion o f ga llb ladde r con ten tsa fte r the firs t s tages o f d is in teg ra tion . C omm on ly , a c loud o r

slurry o f fragm en ts occu rs in w h ich rem a in ing s tones m ay be

h idden . The re fo re , subsequen t d is in teg ra tion m ay be incom -

p le te , leav ing la rge r fragm ents . It is a lso poss ib le tha t occa -

s iona l pa tien ts w ith m u ltip le non rad ioopaque p igm en t s tones

w ill be trea ted , s in ce p igm en t s tones w ou ld be d ifficu lt to

d is tingu ish from cho les te ro l s tones . A lthough fragm en ta tion

m igh t w e ll o ccu r, la te r d isso lu tion o f fragm en ts by b ile ac id s

m igh t no t.

In th is rega rd , the ro le o f o ra l b ile ac id ad ju van t the rapy fo r

d is so lv ing fragm en ts o f cho le s tero l ga lls tones cannot be ove r-

em phas ized . O ra l b ile ac id the rapy a lone w ith e ithe r cheno -

deoxycho lic ac id and u rsodeoxycho lic ac id o r u rsodeoxy-

cho lic ac id a lone has been show n to d isso lve in ta c t cho le s te ro lga lls tones in up to 25% -40% o f app rop ria te ly se le c ted pa -

tien ts but gene ra lly on ly a fte r a cou rse o f the rapy requ iring

1 8 -24 m on ths . The m echan ism o f d isso lu tion com b ines bo th

inh ib itio n o f hepa tic cho le s te ro l syn thes is lead ing to cho les -

te ro l desa tu ra tion o f ga llb ladde r b ile and a d ire c t m echan ica l

m ice lla r and /o r liqu id crys ta l d isso lu tion o f the su rfa ce o f the

ga lls tone its e lf. Fu rthe r, a c lea r co rre la tion ex is ts be tw een

ga lls tone (o r fragm en t) s ize and the ra te o f d isso lu tion , w ith

d is so lu tion occu rring m o re rap id ly a t the sm a lle r s izes bo th in

v ivo [4 ] and in v itro [5 ]. T hus , the m echan ica l e ffe c t o f

fragm en ta tion o f the ga lls tones by ESW L se rves to in c rease

su rfa ce a rea exposed to the d isso lv ing p rocess , g rea tly en -

hanc ing the speed w ith w h ich the to ta l ga lls tone bu rden

d isappea rs (F ig . 1 ). Indeed , w h ile the m anu fac tu re rs speak o fad ju van t o ra l b ile ac id the rapy , the gas troen te ro log is ts tend

to in s is t tha t E SW L is the ad juvan t, m e re ly acce le ra ting w ha t

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A JR :15 0 , Ju ne 1988 GALLSTONE ESW L 1233

is fundam en ta lly b io chem ica l chem o lys is the rapy . The im pa -

tien t in te rven tiona lis ts am ong us even speak o f a s ing le sk inny

need le in je c tion o f m ethy l-te rt-bu ty l e the r in to the ga llb ladde r

fo r p rom pt trea tm en t o f ga lls tones .

W hat abou t the longe r-te rm im p lic a tions o f leav ing the

ga llb ladde r in p la ce? W hen o ra l b ile ac id s a re used as p rim a ry

the rapy and the drug is d iscon tinued a fte r s tone d isso lu tion ,re cu rrence can be expec ted in up to 50% o f pa tien ts w ith in

2-3 yea rs [4 ]. The inev itab ility o f ga lls tone recurrence caused

by res idua l deb ris in a m e tabo lica lly d iso rde red m ilieu is w e ll

re cogn ized and ce rta in ly is no t fo rgo tten by the th rea tened

b ilia ry su rgeon who cou ld end the m a tte r w ith a cho lecys tec-

tom y . In the sho rt fo llow -up s tudy done by Sackm ann e t a l.

[1 ], on ly one pa tien t had a recu rrence a fte r ESW L , bu t the

s tones then d isappea red a fte r re trea tm en t w ith ora l d rugs . In

orde r fo r ESW L to rem a in a m ean ing fu l long -te rm a lte rna tive

to cho lecys tec tom y, m o re de fin itive m easu res w ill be neces -

sary to p reven t re cu rrence . These cou ld in c lude d ire c t m e -

chan ica l, chem ica l, o r caus tic ab la tion o f the ga llb ladde r o r

pe rhaps , lik e the cu rren tly popu la r da ily asp ir in reg im en fo r

preven tion o f hea rt a tta c ks , a da ily o ra l b ile ac id p ill fo re vera f te r.

W ha t about new e r deve lopm en ts and the comm erc ia l com -

pe titio n? T he resu lts now be ing ach ie ved in M un ich w ith the

newe r D o rn ie r litho tnp to r (M PL -9000 ) are supe rio r to those

ach ieved in the firs t 1 75 pa tien ts , pa rticu la r ly w ith rega rd to

the am oun t o f anes the tic requ ired . Indeed , som e 75% o f the

pa tien ts in M un ich a re now trea ted w ith on ly an IV ana lges ic .

T h is advance is ach ie ved by use o f w ide r-ape rtu re e llip so id s

fo r sha rpe r fo cus o f the shock wave in tissue and m o re

e ffic ien tly des igned e lec trodes . In com b ina tion , these e llip -

so id s and e lec trodes reduce the am oun t o f p ressu re depos -

ited in supe rfic ia l tissues and thus reduce the sensa tion o f

pa in .

The reduc tion in pa in , e spec ia lly w hen com pa red w ith c la s-s ica l rena l litho tr ip sy (w h ich usua lly requ ire s a gene ra l anes -

the tic ), has becom e the indus try s tanda rd and appea rs to be

one o f the m a jo r new c lin ica l e lem en ts accom pany ing the

in troduc tion o f ga lls tone ESW L . Indeed , m o re or le s s a ll o f

the five o r s ix m a jo r m anu fac tu re rs a re o ffe ring second -

gene ra tion litho tr ip to r sy s tem s tha t a re no t on ly d ry o r tub le ss

bu t tha t p rom ise va ry ing deg rees o fanes the tic -free litho tr ip s y .

Fo r exam p le , the L ithos ta r s ys tem manu fac tu red by S iem ens

(Ise lin , N J) reduces anes the tic requ irem en ts by p roduc ing

lowe r-pow e r shocks on its e le c trom agne tic shock gene ra to r.

R esp ira to ry ga ting of the shock d ischa rge com b ined w ith

l oca l anes the tic a llow s m os t pa tien ts w ith rena l s tones to be

trea ted as ou tpa tien ts . T echnom ed (D anve rs , M A ) a lso uses

a spa rk /d ischa rge gene ra to r w ith a spec ia lly des igned low -p ressu re e llip so id and e lec trode com b ina tion . Th ree com pa -

n ie s (E dap , B os ton , M A ; W o lf, R osem on t, IL ; and D iason ics ,

M ilp ita s , C A ) use a p iezo-e le c tric shock sou rce , and a ll have

e ithe r show n o r p rom ised little o r no pa in sensa tion w ha tso -

ever; thus , th e p rocedu re w ou ld requ ire no ana lges ic . O n the

o the r hand , it is no t ye t c lear w he the r such sys tem s can

dup lica te the ex trem e ly h igh success ra te o f ga lls tone frag -

m en ta tion and ga llb ladde r c lea rance a lready docum en ted by

Dom ie r. P re lim ina ry unpub lished da ta em e rg ing from Eu rope ,

espec ia lly from the p iezo un its , s ugges t tha t fragm en t s izem ay be la rge r and the re trea tm en t ra te h ighe r w ith bo th k idney

s tones and ga lls tones . A t p resen t, it is unc lea r w he the r th is

w ou ld rep resen t a c lin ica lly s ign ifican t d iffe rence in te rm s o f

biliary co lic and com p lic a tions o f fragm en t obs tru c tion . If the

crea tion o f num e rous res idua l fragm en ts does no t cause

acu te p rob lem s and if fo llow -up trea tm en ts a re pa in le s s and

less cos tly and adm in is te red on an am bu la to ry bas is , the

cho ice m ay be no m o re than a m a tte r o f s ty le .

W ha t abou t the ro le o f rad io log is ts ? A ll ga lls tone litho trip sy

w ill requ ire rea l- tim e sonog raph ic gu idance , and m ost m anu -

fa c tu re rs a re now p rov id ing sonog raphy fo r rena l litho tr ip sy

as w ell ( ir rad ia tion conce rns ). B ecause of the m ultid isc ip lina ry

in teres t in ga lls tone d isease , it is un lik e ly tha t rad io logy o r

any o the r s ing le spec ia lty w ill to ta lly dom ina te b ilia ry app lica -tions . Indeed , g iven the com p lex ity o f fa c to rs a ffe c ting these

new trea tm en t m e thods , it is p robab ly no t in the bes t in te res ts

o f sc ien tific advancem en t fo r one spec ia lty to dom ina te the

fie ld . R ad io log is ts shou ld , how eve r, s trive to pa rtic ipa te as

c lin ica l im age rs and consu ltan ts du ring the trea tm ent p rocess ,

as they have trad itiona lly done in o the r m u ltiphys ic ian proce -

dures . If the re is a la ck o f in te res t by o the r spec ia lties , then

o f cou rse the ab ility to sonog raph ica lly ta rge t the ca lcu lu s fo r

shock -w ave adm in is tra tion w ould lead to g rea te r u ltim a te

con tro l. U ro log is ts do ing sonog raph ica lly gu ided rena l litho -

trip sy have repo rted a 6 -w eek lea rn ing cu rve to use rea l- tim e

sonog raphy fo r s tone lo ca liz a tion . C e rta in ly , m ost rad io log is ts

can lea rn to push the bu tton in the sam e am oun t o f tim e .

W ith m a rke t es tim a tes tha t 500-750 m o re litho tr ip to rs m aybe ins ta lled in the U n ited S ta tes , the re shou ld be room fo r

m any o f us to becom e d ire c tly in vo lved .

REFERENCES

1 . Sackm ann M , D e lius M , S aU erb rU ch T , e t a l. S h oc k-w ave litho trip sy o f

g allb la dd er s to ne s. Th e firs t 1 75 p at ien ts . N ew EngI J M ed i 988 ;31 8:

393-396

2 . S au erb ru ch T , De liu s M , Paum ga rtn e r G , e t a l. F ra gm en ta t ion o f g a lls ton es

by e xtraco rp o re a l sh ock w aves. N ew Eng l J M ed i 986 ; 314 : 818 - 822

3 . R om e G rou p fo r E pid em io logy a nd P re ve ntion o f C ho le l ith ias is (G RE PC O).

R ad io lo gy ap peara nce o f g a lls to ne s a nd its re la t ion sh ip w ith b ilia ry s ym p-

toms . D ig D is Sc i i 987 ; 32 ( 4 ) : 349 - 353

4 . W a rd A , B ro gde n R N , H ee l R C , e t a l. U rs od eo xycho lic ac id : a re v iew o f its

p ha rm aco log ica l p ro pe rtie s an d th e ra pe u tic e fficac y . Drugs 1984 :27 :

95-131

5 . N eubran d M , S auerb ruch T , S te l laa rd F , Pa um ga rtne r G . In v it ro ch o le s te ro l

ga l ls to ne d isso lu tio n a fte r fra gm en ta t ion w ith sho ck wa ves . Diges t ion

i 986 ;34 :51 - 59