William Rendon

E. Torres, C. Nelson,

MD MD

Extracorporeal of Gallstones: Follow-up

#{149} Harvey

William

#{149}

in

terms:

Gallbladder, US studies,

Gallbladder, 762.1299

Radiology I

From

calculi, 762.1298

762.289 #{149} Lithotnipsy,

1991; 178:509-512 Stone

Treatment

Center,

Craw-

ford Long Hospital of Emory University, 550 Peachtree St NE, Atlanta, GA 30365. From the 1989 RSNA scientific assembly. Received June 1, 1990; revision requested July 17; revision neceived September 14; accepted September 20. Address C

RSNA,

reprint

1991

requests

to

WET.

#{149} R.

Carter

the successful of extracomporeal

FTER

Davis,

MD

#{149} Bruce

MD

R. Baumgartner,

lithotripsy

(ESWL)

for

introduction shock wave

had

partially

less

rim

the

eter was determined

treatment

of nephrolithiasis in 1984, investigatons at the Klinikum Gnosshademn, Munich, began to evaluate the use of shock waves for the treatment of gallstones. In 1986, the first patient was successfully treated with ESWL (1). In 1988, Sackmann et a! (2) meported the results of ESWL in their initial 175 patients sis. The American

with cholelithiaexperience with

the MPL-9000 lithotriptor (Domnier Medical Systems, Munich) began in May 1988. Current protocols are designed

to evaluate

the

safety

and

effi-

cacy of ESWL in the fragmentation of gallstones. In addition, in a randomized controlled fashion, the need for adjuvant therapy with an orally administered

chemolytic

agent,

urso-

deoxycholic acid (UDCA), is being studied. Herein, we report our mesults, including those from the 6month

follow-up,

patients

from

treated

with

our

first

141

ESWL.

AND

.

in

diameter).

had had

Screening and

inclusion

and

exclusion

criteria

for

candidates for ESWL are presented in Table 1. We studied 141 patients, 92 women and 49 men, aged 22-87 years (mean, 49 years). Fifty-five patients were anesthesia risk assignment class I, 73 were class II, and 13 were class III. The patients weighed 47-143 kg (mean, 80 kg). The maximum

number

treatment

permitted

1,500.

All patients

of shock

waves

to fit

underwent

administered

ESWL analgesia

with and

sedation with fentanyl citrate and midazolam hydrochloride. As part of the double-blind study, 74 randomly selected patients received UDCA and 67 received placebo. The UDCA (Ursofalk; Jacobus Pharmaceuticals, Princeton, NJ) was usually

given

as a single

dose

at bedtime

10 mg/kg pen day). One hundred twenty patients had noncalcified gallstones and

by

patients

and

(21%)

12 patients

(8%)

anesthesia

risk

assignment

I-Ill. An electrocardiogram was to exclude arrhythmia. Baseline included analysis of aspartate

aminotransferase,

alanine

ase, alkaline

aminotnansfer-

phosphatase,

bilirubin,

amy-

lase, lipase, blood urea nitrogen, and creatinine levels, prothrombin and partial thromboplastin times, hematocrit volumes, as well as a platelet count. Pregnancy tests were performed in all premenopausal women who had not undergone a hysterectomy. Radiographic screening included plain film of the abdomen to detect gallstone calcification, chest

radiography,

to evaluate

oral

the

ultrasound

biliary

tree

to identify and and a double-dose

gallstone(s)

was

gall-

(Telepaque;

Pharmaceuticals,

evaluate gallbladder cy of the cystic duct.

and

quantify the (reinforce-

cholecystography

Winthrop

New

function The

York)

to

and paten-

diameter

determined

of the

with

use

of

US.

Follow-up

Study

Follow-up

was

sonographicaily

Procedure

into

classes obtained studies

per

in the protocol

or

diam-

Patients underwent clinical, laboratory, radiographic screening. Patients had

ment)

The

(3 mm

Gallstone

Twenty-nine

two gallstones, three gallstones.

bladder and gallstone(s),

Patients

gallstones

nidus).

measuring the largest diameter. Among the 141 patients, 100 (71%) had solitary stones (74 had stones 20 mm or less in diameter and 26 had stones 21 mm or more

(US)

METHODS

calcified

or central

baseline

PATIENTS

intravenously

the

MD MD

Shock Wave Lithotripsy Results and 0-month 141 Patients’

A study of biliary shock wave lithotripsy of gallstones sponsored by Dornier Medical Systems, Munich, began in the United States in May 1988 to evaluate the efficacy and safety of extracorporeal shock wave lithotnipsy (ESWL) and the need for adjunctive therapy with ursodeoxycholic acid (UDCA). One hundred forty-one symptomatic patients with one to three gallstones 5-30 mm in diameter were randomized to treatment. One week before ESWL, patients were given either UDCA or placebo. This treatment was continued for 6 months. All patients underwent follow-up at predetermined intervals. According to the protocol, re-treatment for fragments larger than 5 mm in diameter could be performed only at 6 weeks; 26 (18%) of the 141 patients were retreated. At 6 months, the stone-free rates for single stones were as follows: patients with noncalcified stones receiving UDCA, 29%; patients with noncalcified stones receiving placebo, 24%; and patients with partially calcified stones receiving either UDCA or placebo, 6%. No significant difference was noted between the UDCA and placebo groups. At 6 months, the stone-free rates in patients with single, noncalcified stones 20 mm or less in diameter were 40% (UDCA) and 32% (placebo), which is superior to rates for those with solitary, noncalcified gallstones 21-30 mm in diameter and those with two or three stones. Index

V. Steinberg, J. Casarella,

termined tients (n

for two 65)

occurred

nights;

were

tient months

subsequent

seen

at 6 weeks,

for

one

US 1 day

subsequently

basis

patients

for

underwent

were

prede-

The initial in the hospital

hospitalized

patients and

at intervals

by the protocol. = 76) remained

3 months,

follow-up

clinical

(n

night.

after on

pa=

All

ESWL

an

out-pa-

and

6

evaluation,

(8-

Abbreviations: (85%) 21 (15%)

wave

lithotnipsy,

ESWL UDCA

=

extracorponeal ursodeoxycholic

shock

acid.

509

abdominal

sonography,

studies.

At

raphy

and

6 months,

was

oral

performed,

laboratory

5.4

cholecystog-

as specified

by the

protocol.

Drug

Study

The

treatment

protocol

with

UDCA

or

placebo was continued for 3 months after complete dissolution of stones. Patients were considered stone free if US revealed no stone fragments. The drug study was discontinued nancy.

in one

patient

due

to preg-

mm).

Fourteen

Procedure

All patients

MPL-9000 scnibed treated

patient

position. line

with

use of a

as previously

was treated

The

gallbladder

initially

localized

US transducer

ed arm. built

treated

de-

(3). All patients but one were while in the prone position; the

latter were

were

lithotniptor,

for

refused.

the largest re-treatment mm). The treatment mm). At 3

gallstone fragment before was 9.5 mm (mange, 5-15 mean diameter after mewas 4.0 mm (range, 3-9 months, five patients were

mm).

stone

and

At

3 months,

free

of stones

turn

for

built

A second,

into

quently

into

the

therapy

Once

an articulat-

head

was

mean

fragment

(range,

2-12

the

was

4.0 mm

tients

who

did

not

and

one

for

follow-

stones.

All 58 patients in this group underwent follow-up US the day after ESWL, which revealed that 50 pa-

larger

than

5 mm

in diameter

re-

RESULTS The 141 patients were divided into three groups: (a) those with noncalcified gallstones receiving ursodeoxycholic acid (n = 62), (b) those with noncalcified gallstones receiving placebo (n = 58), and (c) those with partially

calcified

gallstones

difference

in

the

number, size, and volume three groups (Table 3). Patients Gallstones

mean

among

the

with Noncalcified Receiving UDCA

while

19 had

from 510

had

fragments

2 to 19 mm Radiology

#{149}

that

in diameter

or less

Table 2 Number and Type

of Gallstone

No. of Gallstones

Receiving

One 2Omm

21mm Two Three

pacemaker

or ar-

rhythmia common

Known

bile duct

stones

in

Densely

calcified stones cyst or hemanglo-

Hepatic

ma Vascular

in shock wave path aneurysm in

wave path in shock wave path

shock Lung

Any indication istence

for the cx-

of a pigment

stone

in 141 PatIents with

Noncalcified

UDCA

Stones

Receiving

Patients

Placebo

with

Partially Calcified Stones

45

42

33 12 11

31 11 13

13 10 3 5

6

3

3

3

Comparison

of Gallstone

Data Among Patients

with

Patient

Groups

Noncalcified

Stones

Patients

with

Partially Receiving UDCA (n62)

Receiving (n58)

Placebo

Calcified (n21)

Stones

fragments

larger than 5 mm in diameter. At the 6-week follow-up, two patients were stone free; 13 patients did not return for follow-up. The remaining 47 patients

five coagulation Pregnancy Cardiac

diameter and eight had fragments larger than 5 mm in diameter. At 6 weeks, two patients were stone free; two did not return for follow-up. The remaining 54 patients had fragments that averaged 4.3 mm in diameter (mange, 2-15 mm). Ten patients were

Table

All 62 patients in this group underwent follow-up US the 1st day after ESWL. US revealed that 43 of these patients had fragments 5 mm or less in diameter,

5 mm

Patients in preoperative anesthesia risk assign. ment class I-Il! Clinically relevant defec-

Exclusion

Patients

receiving (n 21).

either UDCA or placebo Information on stone burden of the three groups is presented in Table 2. Results of a student t test showed no significant

fragments

colic

means of US

with Noncalcified Receiving Placebo

had

me-

dus allowed) Proof of functioning gallbladder at oral cholecystography Detection of stones by

or

of 1,500 shock waves per treatment can be administered at 14-23 kV. The number of shock waves administered in our study ranged from 926 to 1,500 (mean, 1,439).

tients

47

of the mm

and Exclusion

Biliary

as fol-

Patients Gallstones

ments main.

for Inclusion in the Study Criteria

was

allows one re-treatment at 6 the initial treatment if frag-

diameter was 3.7

One to three gallstones Stone diameter 5-30 mm Nonialcified stones (3mm rim or central ni-

targeted with the in-line system, shock wave therapy began. According to the American Dornier protocol, a maximum

The protocol weeks after

for

1

Inclusion

one stone 20 mm two patients, two three

return

of

remaining

Criteria

calculanumbers

were

not

the

of

diameter

Criteria

Pa-

in these sizes and

patient,

did

diameter

mm).

return

patients

six

mean

the mean fragments

Table

free

patients,

stones;

subse-

the gallstone(s)

stone

return for followthe remaining 39

two

The

Among

patients, maining

the mean fragments mm). At 6

were

free

ne-treatment,

follow-up.

and seven did not up (Fig 3). Among

lows: 13 patients, less in diameter;

US transducer

to me-

2). Among

the remaining 51 patients, diameter of the remaining was 3.4 mm (range, 2-22 16 patients

were

failed

(Fig

in stone-free

gallstone(s)

patients

five

follow-up

and

in-line,

used.

six

and

up are not included tions. Initial stone

an out-of-

eli-

whom

in the supine with

were

eligible

months,

Lithotripsy

patients

gible for re-treatment; one patient mefused (Fig 1). The mean diameter of the largest gallstone fragment before me-treatment was 13 mm (mange, 6-29 mm); the mean diameter after retreatment was 6.7 mm (range, 3-23

ranged

No. of stones Mean no. of stones persubject

Mean size of stones (mm) Mean volume of stones (mm3)

85

77

l.40.7

13.4 2,458.2

1.3±0.6

± 7.1 ± 3,633.2

14.3 2803.7

± 7.3 ± 3,610.5

32 1.5±0.7

12.5 1,959.8

± 6.7 ± 2,686.0

(mean, February

1991

% Stone

Free

40 % Stone

% Retreatment

Free

25 30 20 20 15 10

_\\II1I.

10 0

.

6 weeks

3 months Time

5 Figure Stone

and

Types

Number

of Patients

and Sizes

1ypes

of Stones

UDCA,

2.

Figures centage

1, 2. (1) Percentage of all patients with of patients free of gallstones at 6 months,

patients gallstones

with noncalcified gallstones receiving placebo, Ca

one gallstone smaller three gallstones.

than

20 mm

striped

cified

gallstones separated

receiving patients with

UDCA, partially

in diameter,

dotted

re-treated at 6 weeks by treatment groups.

and

(2) per-

NCaLJ noncalcified Solid bans striped bars

patients with calcified gallstones. bars = two gallstones, NCaP

Percentage

bars

gallstones patients

bars

free of

bans receiving

patients

patients

with

noncal-

receiving placebo, dotted with partially calcified gall-

stones.

=

= =

did the

not return remaining

fragment (range, 40

of patients

gallstones at 6 months. Solid with noncalcified gallstones

0 1.

3.

6 months

Patients

tient mm

2-8

for follow-up. 20 patients,

diameter mm).

the

Among mean

was 3.9 mm The stone-free

had an initial in diameter.

pa-

single

stone

8.0

for

entry into had biliary

35 Adverse

30 25

the

20

Events

As a requirement study, all patients

lic. Biliamy of patients

15

colic was detected during the 6-month

study (Fig 4). A single episode iamy colic occurred in 35 patients,

10

two episodes three or more

5 NCaU

0

NCaP

tients.

Ca

Time Figure

4. Treatment group and patient experienced colic. NCaU NCaP = patients with noncalcified calcified gallstones. Solid bars day

after

treatment,

bold-face

number

of patients

patients

with

experiencing

noncalcified

biliary gallstones

gallstones receiving placebo, day 1, vertically hatched bars

vertically

hatched

bars

colic

versus

receiving

time

UDCA,

checked

bars

colic

was

agent patient

and a mild analgesic had clinical signs during

2-14 mm). At 6 months, 13 were stone free and five did

not return for follow-up. remaining 40 patients, ment diameter was 4.9

Among the the mean fragmm (range, 2-

13 mm). The patients who did not meturn for follow-up are not included in these calculations. The initial stone sizes and numbers of the stonefree patients were as follows: 10 patients,

one

ameten

stone

and

20 mm

three

or less

patients,

in di-

UDCA and nine received placebo. performed the 1st day after ESWL vealed 18 patients to have fragments 5 mm

or less

stone fragment before was 8 mm (mange, 3-9

months,

with

Partially

Among

the

21 patients

tially

Volume

calcified

178

Calcified with

gallstones,

Number

#{149}

2

and

three

to

have fragments larger than 5 mm in diameter. No patient was stone free at 6 weeks. Five patients were eligible for ne-treatment at 6 weeks. The mean diameter of the largest gall-

mean diameter 4.4 mm (range,

two

stones.

Patients Gallstones

in diameter

US me-

one

me-treatment mm). The

patient

pan-

mm

(mange,

2-7

mm).

At

12 received

one

patient

was

stone

free

one

first

agent. No of pancre-

6 months.

En-

cholangiopanperformed in

due to severe right pain; no common fragments were seen

No patient

required

a

of liver

in the size was detected

injury

or increase

of the common in any patient.

bile

duct

Cutaneous (n

petechiae were seen in 66) of the patients after The petechiae were generally

was

mild and were not present at the follow-up visit. Microscopic or gross hematumia was seen in 50% (n 70) of the patients after ESWL. During the 6-month study period, results of

3.2

blood

chemistry

tions

of aspartate

re-

6 months,

and

evidence

ESWL.

ceiving placebo was stone free. Among the remaining 20 patients, the mean fragment diameter was

time.

an

sphinctemotorny during the first 6 months. One patient underwent a cholecystectomy for severe biliary colic at 5 months. No sonographic

47%

after me-treatment 2-9 mm). At 3 re-treated

at that

with

antispasmodic

the

eight patients upper quadrant bile duct stone

(mange, patients

generally

treated

administered

doscopic retrograde cneatography was

6 months.

was

easily

orally

atitis

Ca = patients with partially 8 weeks, dotted bars = 1

3 months,

and

of bil-

in 30 patients, and episodes in 24 pa-

Biliary

mild

co-

in 25%

9% (n

12), alanine

tests

showed

eleva-

aminotransferase

in

aminotransferase Radiology

511

#{149}

in 10% (n = 14), amylase 9), and lipase in 7% (n tients.

in 6% (n 10) of the

pa-

DISCUSSION Our results show that ESWL performed with current treatment panameters in selected symptomatic patients with gallstones is a safe and moderately effective therapy. Our results are similam to those published by other investigatoms (3-6), but they differ from those of the Domnien National Cooperative Gallstone Study (7) of patients with noncalcified gallstones in which a statistical difference in the stone-free rate was noted for patients receiving UDCA versus those receiving placebo. In our study,

no difference

in the

at 6 months

than

that

of pa-

tients with noncalcified stones. Initial stone size is an important terminant of the time it takes until patient is stone free. Patients with single

gallstone

20 mm

or less

dea

a

in diam-

eter, whether receiving UDCA or placebo, had a faster clearance rate at 6 months than did patients with single stones 21-30 mm in diameter or patients with two or three gallstones. The difference in stone clearance between single gallstones 20 mm or less in diameter and larger solitary or multiple noncalcified stones is most likely due to the difference in initial gallstone volume. A recent in vitro study (8) suggests that when corrected for volume, single stones are more easily shattered into fragments 5 mm or less in diameten than are multiple gallstones. The implication is that more shock wave energy is needed to achieve the same results in the treatment of patients with multiple stones versus a single gallstone with a similar volume. The size and number of fragments remaining after ESWL are also believed to be a determinant in the time it takes until a patient is stone free. Sackmann et al (2) have suggested that patients with a single, noncalcified gallstone 20 mm on less in diameter have a faster clearance rate due to the smaller size of fragments after ESWL than do patients with a single stone larger than 21 mm in diameter on with multiple stones. Slower clearance rates in patients with partially calcified and larger

512

Radiology

#{149}

ance

tion.

ny

It can

be difficult

to target

mdi-

vidual ESWL,

gallstone fragments during often due to an obscuring cloud

caused

by cavitation

effects

and

is thus

used

to alter

the

position

of the stone rather than to fragment it. These factors can influence the outcome of lithotnipsy for all stones, regandless of mass or composition. We believe that gallstone fragment clearance primarily occurs within the immediate postlithotnipsy period (4-6 weeks), beyond which a decrease in fragment number or size is most likely due to the effect of UDCA or naturally occurring bile acids and to the further passage of smaller gallstone fragments. The frequency of adverse events aften ESWL

is low.

The

higher

incidence

of biliary colic in our study and the Domnier National Biliamy Lithotnipsy Study (7) compared with the study by Sackmann et al (2) may be due to the differences in the study definition of biliary colic. In our study, all patients with any discomfort in the right upper quadrant

were

considered

at 6 months

ies that similar

to have

We believe

that

if the Food

cacy

in the United will

be

and

European

Differences

U.S. protocol restricts the number and voltage of shock waves in the American study (ie, 1,500 shock waves at 16-23 kV). With the current protocol, the best 6-month clearance rate is achieved with single, noncalcified gallstones that are 20 mm on less in diameten. The stone clearance rate at 6 months in the German study and the U.S.

Dornier

study

are

similar

creased

shock

creased

number

higher tation

voltage) rate and

wave of

energy shock

(ie, waves

and

Drug

States

shock effi-

the

and

in Germa-

CONCLUSION It appears

that

technology

ESWL

can

with

spark-gap

successfully

fragment

the vast majority of gallstones. Patients with solitary, noncalcified gallstones 20 mm on less in diameter dates for the procedure. solitary

gallstones

are ideal candiPatients with mm in diame-

21-30

ten and those with two or three gallstones will need to undergo additional treatments, higher-power treatment,

longer

dissolution

ministered

times

with

chemolytic

cedure

with

US expertise. are disappointing

the initial

report

ad-

The

pro-

and

requires

The

results compared

from

on

orally

agents.

is time-intensive

significant our study

of

the Gros-

shademn group (2). We believe that the procedure is still in its infancy and much has yet to be learned. We antici-

pate

improved

States

results

as the

in the United

procedure

is modified

to

optimize treatment parameters, as has been done by European investigators. U References 1.

Sauerbruch T, Delius M, Paumgartner G, et al. Fragmentation of gallstones by extracorporeab shock waves. N Engl J Med 1986;

2.

Sackmann M, Delius M, Sauerbruch Shock-wave lithotnipsy of gallbladder stones: the first 175 patients. N EngI

314:818-822.

3.

4.

1988; 318:393-397. Ponchon T, Barkun

AN,

Pujol

T, et al. J Med

B, et al.

Gall-

stone disappearance after extracorporeal lithotripsy and oral bile acid dissolution. Gastroentenology 1989; 97:457-463. Hood AK, Keightley A. Dowling RH, Dick JA, Mallinson CN. Piezo-ceramic lithotripinitial experience 1:1322-1324.

in

5.

ElI CH. Kerzel W, Heyder N, et al. Piezoelectric lithotripsy of gallstones. Lancet 1987; 2:1149-1150.

6.

Steinberg

7.

8.

Tomes

of gallstone

lent stone 509. 9.

HV,

WE,

Nelson

RC.

Gall-

bladder lithotnipsy. Radiology 1989; 172:711. Schoenfield U, Berci C, Carnolvale RI, et al. The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallstones: the Dornier National Biliary Lithotnipsy Study. N Engl J Med 1990; 323:1239-1274. Tomes WE, Baumgartner BR, Jones MT. Ndson RC. Biliary lithotnipsy: an in vitro analysis

when

comparable parameters are used. In Europe, the physician has more flexibility to change treatment parametens. Unpublished data from the Grosshadern Klinikum group (9) using in-

stud-

similar.

sy of gallbladder stones: 38 patients. Lancet 1988;

U.S.

with

treatment parameters of the United States.

Administration allows increased wave and voltage parameters,

bili-

ary colic, which tended to be mild (ie, easily treated with a mild analgesic agent and an antispasmodic agent). While hematuria occurred in 50% of the patients, it was generally transient.

compared

employ to those

fnag-

ment debris. Increasing gallstone fragmentation produces a fragment line, the length of which does not allow all fragments to be simultaneously placed within the shock wave focus and treated. The gallstone(s) often moves with shock waves and changes position, producing a net loss of energy to the stone. Energy

stone-free

mate was seen in patients with noncalcified gallstones receiving UDCA and those receiving placebo. In both studies, the stone-free rate in the patients with partially calcified gallstones, regardless of whether they were mccciving UDCA or placebo, was substantially lower

stones and groups of stones may also be due to US imaging difficulties encountered by the treating physician during the ESWL procedure, during which gallstones or their fragments often overlap, preventing adequate localization, targeting, and, thus, fragmenta-

Sackmann M. nich experience.

delphia Philadelphia.

fragmentation

volumes.

New lessons Presented

Symposium March

for

Radiology

from at the

on Biliary 1-3,

equiva-

1990;

177:507-

the Mu2nd Phila-

Lithotnipsy,

1990.

inat a

show a better fragmenan increased stone clear-

February

1991