GASTROENTEROLOGY

1992;103:311-316

Extracorporeal Shock-Wave Lithotripsy and Ursodiol Versus Ursodiol Alone in the Treatment of Gallstones ATILLA ERTAN, RICHARD E. HERNANDEZ, JOHN R. GESHNER, and MARTIN S. LITWIN Section of Gastroenterology, Department Medical Center. New Orl&s, Louisiana

of Radiology, and Department

The efficacy and occurrence of adverse effects after two forms of treatment were compared in 111 patients with hiliary colic and radiolucent gallstones in this prospective, nonrandomized study. Fiftyfour patients received extracorporeal shock-wave lithotripsy (ESL) plus ursodiol, and 57 patients received ursodiol alone. Among patients with a single stone (5-20mm in size), no patient treated with ursodiol alone had a stone-free gallbladder at 6 or 12 months after treatment; of those treated with ESL plus ursodiol, 15 of 24 patients (63%) had a stonefree gallbladder at 6 months and 17 of 20 patients (85%) at 12 months. For patients with multiple stones (with an aggregate diameter of 130 mm), the incidence of a stone-free gallbladder was 2 of 43 patients (5%) at 6 months and 8 of 35 patients (23%) at 12 months in the ursodiol treatment group. In the ESL plus ursodiol group, the incidence of a stonefree gallbladder was 7 of 22 patients (32%) at 6 months and 8 of 20 patients (45%) at 12 months. Two patients in the ESL plus ursodiol group (4%) and 13 patients in the ursodiol group (24%) underwent cholecystectomy. Both patients in the ESL plus ursodiol therapy and 4 patients in the ursodiol group had emergency cholecystectomies because of acute cholecystitis. The remaining 9 patients in the ursodiol group had elective cholecystectomies. In this nonrandomized, prospective study, ESL plus ursodiol treatment produced stone-free gallhladders at a faster rate than ursodiol alone in patients with either single or multiple gallstones. he treatment of gallstones using extracorporeal shock-wave lithotripsy (ESL) and adjuvant medical therapy with oral bile acids in selected patients was first reported in 1986.’ Since then ESL has become an exciting option for the treatment of radiolucent gallstones in selected cases.‘-” In the German experience, which has been the most extensive, Dornier lithotripters have been used.le3 Approximately 78% of the patients were stone free 1 year after ESL

T

RICHARD

J, CAMPEAU,

of Surgery, Tulane University

with adjuvant bile acid therapy. The most severe complication has been mild to moderate acute pancreatitis, which has developed in ~2% of the patients treated. More than a dozen different lithotripters have been developed, nine of which are currently being tested under investigational protocols in the United States. Most of the reported American experience with ESL for treatment of gallstones has been from investigators using the Medstone (Irvine, CA) STS lithotripter,4j6s7 the EDAP LT-01 lithotripter (EDAP International, Boston, MA) ,I0 and the Dornier lithotripter (Dornier Medizin Technik GmbH, Munich, Germany).” Efficacy and adverse events have been similar to those reported in the European trials,4,6,7,10

Dissolution therapy with oral bile acids alone has also been shown to be an effective therapeutic method for treatment of selected patients with symptomatic gallstones.‘3-‘7 There has been no published study, to the authors’ knowledge, that compares combination treatment of ESL plus ursodiol with ursodiol alone. The current prospective study was therefore performed to compare the efficacy and the occurrence of adverse events of ESL plus ursodiol with the use of ursodiol alone for treatment of selected patients with gallstones. Materials and Methods Patient Population

and Study Protocol

In the present prospective and nonrandomized study, a total of 387 patients with gallstones were screened at the Tulane University Medical Center (TUMC) between July 1988 and December 1989; 54 (14%) were selected for

study using a Food and Drug Administration (FDA)-approved investigational protocol for ESL and ursodiol therapy (Table 1). Similar criteria, excluding the last three, were used to select patients for ursodiol therapy alone. Patients with multiple stones (six or less) with an aggregate 0 1992 by the American Gastroenterological Association 0016-5085/92/$3.00

312

ERTAN ET AL.

GASTROENTEROLOGY

Table 1. Selection Criteria for ESL Plus UrsodioJ Therapy of Patients With Gallstones History of biliary colic Solitary radiolucent gallstone > 4 mm and 5 20 mm or multiple stones 5 30 mm in maximum diameter” Gallbladder visualization on OCG No stone calcification on cone-down x-ray No bile duct obstruction, cholangitis, pancreatitis, cholecystitis, or significant liver disease No bowel gas, lung tissue, vascular aneurysms, or cysts in shock-wave path No bleeding disorder No cardiac pacemaker “Determined on aggregate diameter by ultrasonography.

diameter of 130 mm determined by ultrasonography were included in either treatment group. Patients with more than six stones (20 patients] were included only in the ursodiol alone group. The study protocol was approved by the TUMC Institutional Review Board, and informed consent was obtained from each patient treated by ESL and ursodiol. Although detailed study protocol information was given, informed consent was not obtained from patients treated with ursodiol alone, which is FDA approved for commercial use. Demographic data of the two groups of patients selected are shown in Table 2. In the ursodiol alone treatment group, 27 patients with multiple stones had six or less stones and 20 patients had more than six stones. In this latter subgroup, 8 patients had floating stones determined by oral cholecystography (OCG). Twenty-nine of the patients treated with ESL plus ursodiol in this study have been reported previously in a national multicenter study.6 All patients in both treatment groups underwent a pretreatment, complete history, and physical examination by one of the gastroenterologists (A.E. or R.E.H.). Results of complete blood count, serum concentration of blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and serum amylase activity were determined within 48 hours before the start of treatment and at three monthly intervals thereafter until study completion (3 months after complete stone disappearance). Gallbladder ultrasonography was performed within 48 hours before patients were assigned to a treatment category, 24 hours after ESL plus ursodiol therapy, and at three monthly intervals until study completion in both treatment groups. OCG was performed before treatment and at 6-month intervals during the follow-up period in both treatment groups for gallbladder visualization. All radiological studies, including OCG, were read and evaluated by the same radiologist, although not in blinded fashion. All stone diameters were determined by ultrasonography. Common reasons for exclusion from the study were stone(s) with diameters > 30 mm (24%), stone calcification (13%), ambivalent patients (13%), nonvisualized gallbladder by OCG (7%), and asymptomatic patients (5%). External

Shock-Wave

Lithotripsy

The patients assigned to ESL plus ursodiol therapy were treated with a Medstone STS lithotripter (Irvine, CA),

Vol. 103, No. 1

which uses a spark-gap system to generate shock waves for the fragmentation of gallstones. During the procedure the patient lies on the flat-dry table in the prone position. The gallstones are located using a hand-held ultrasound transducer. A cursor on the ultrasound screen is placed at the gallstone site. The operator then instructs the computer to calculate the point of maximum shock-wave impact. At this point the targeted gallstone is in the F, point. During ESL the F, points are relocalized after every 300-400 shock waves to maximize treatment efficacy. The shock waves are electronically synchronized to the patient’s electrocardiogram to prevent the occurrence of a shock wave during the heart’s hyperexcitable phase.” Fourteen of the patients in this group were treated under general anesthesia. After FDA approval of the protocol modification, the remaining 40 patients received only intravenous (IV) analgesia, consisting of 1-2 mg midazolam, 0.625 mg droperidol, 5 pg/kg alfentanil IV bolus, and 0.25 to 1 pg. kg-’ - min-’ alfentanil by continuous IV infusion, depending on the patient’s tolerance. Thirty patients were hospitalized for 1 day after ESL. The last 14 patients were treated on an outpatient basis after FDA approval of this modification in the protocol. Patients were treated by ESL consisting of 1000-2000 shock waves per treatment (mean, 1871) over 45-90 minutes. Ultrasonography was used to guide the position of the stone(s) at the F, point and to monitor the process of fragmentation during and after ESL. We hypothesized that passage of small (~3-4 mm) stone fragments after ESL would be facilitated if patients were fed a high-protein, fatty meal shortly after treatment, so that endogenous release of cholecystokinin would cause gallbladder contraction.‘g~20 Initial stone fragmentation was defined as satisfactory if any one of the following ultrasonographic findings were noted 24 hours after ESL: (a) reduction of the number or size of stones by at least 30%; (b) all residual fragments 1.5 cm Multiple stones (%) cl.5 cm >1.5 cm

54 (14) 39 15 49(24-73) 163(106-256) 27 20 (74)

57 (15) 37 20 53(29-80) 159(104-204) 10

7 (26) 27' 22 (81)

7 (70) 3 (301 47d 39 (83)

5 119)

8 (17)

“Percentage of patients screened who were assigned to each treatment group. bUp to Z-cm diameter solitary stone. “Up to 6 stones; aggregate diameter of all stones, 3 cm. dRepresents 27 patients with 56 stones and 20 patients with >6 stones; aggregate diameter of all stones 5 3 cm.

ESL AND URSODIOL

July 1992

der. Six patients (11%) had stone fragments > 5 mm 3 months after ESL follow-up, and ESL was repeated once only using 2000 shock waves. Stone-free gallbladder was defined as evidence of complete gallstone clearance by at least two successive ultrasonograms obtained 1 month apart. During the patient’s subsequent clinic visit, usually 24 hours after the ESL with IV analgesia, each patient received a questionnaire to assess the degree of pain and discomfort they experienced during the procedure, grading from 0 (no pain or discomfort) to 10 (unbearable pain or discomfort).

Oral Dissolution

IN GALLSTONE

TREATMENT

313

IJ Single Stone

?? Multiple Stones ??All Patients

Therapy

In

the ESL group and in the group treated with ursodiol alone, all patients received ursodiol (Actigall, 8-10 mg +kg-’ - day-‘; Ciba-Geigy, Summit, NJ) at bedtime continuously; patients with complete stone disappearance received ursodiol for an additional 3 months. Stone-free gallbladder was defined as evidence of complete gallstone clearance by at least two successive ultrasonograms obtained 1 month apart. Statistical

VS. URSODIOL

Evaluation

The results are presented as means I SD with ranges. For significance testing, the Wilcoxon rank sum test, Student’s t test, and the x2 test analysis were applied. Results with P < 0.05 were considered significant. Data were also analyzed using the Cox proportional hazards model for censored data. Independent variables included were group, age, gender, number of initial stone(s), and size of stone(s). Race could not be included because there were no blacks in the ESL plus ursodiol group and only one in the ursodiol group. The dependent variable studied was the time to stone-free gallbladder.

Results Initial satisfactory stone fragmentation by ESL occurred in 92% of the patients. The cumulative incidence of patients in whom stone fragments were reduced to