doi:10.1111/j.1440-1746.2009.05828.

GASTROENTEROLOGY

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Single session versus separate session endoscopic ultrasonography plus endoscopic retrograde cholangiography in patients with low to moderate risk for choledocholithiasis
Carlo Fabbri,* Anna Maria Polifemo,* Carmelo Luigiano,* Vincenzo Cennamo, Lorenzo Fuccio, Paola Billi,* Antonella Maimone,* Stefania Ghersi,* Sandro Macchia,* Constance Mwangemi,* Pierluigi Consolo,* Agata Zirilli, Leonardo Henry Eusebi and Nicola DImperio*
*Gastrointestinal and Endoscopy Unit, AUSL Bologna Bellaria-Maggiore Hospital, Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, and Department of Statistics, University of Messina, Messina, Italy

Key words choledocholithiasis, endoscopic retrograde cholangiography, endoscopic ultrasonography. Accepted for publication 20 January 2009. Correspondence Carmelo Luigiano, Gastrointestinal and Endoscopy Unit, AUSL Bologna Bellaria-Maggiore Hospital, Largo Nigrisoli 2, Bologna, Italy. Email: carmeluigiano@libero.it

Abstract
Background and Aim: Endoscopic ultrasonography (EUS) is a minimally invasive diagnostic tool for common bile duct stones (CBDS) and may be used to select patients for therapeutic endoscopic retrograde cholangiography (ERC). The aim of this trial is to compare, in patients with non-high-risk for CDBS, the clinical and economic impact of EUS plus ERC performed in a single endoscopic session versus EUS plus ERC in two separate sessions. Methods: During an 11-month period, all adult patients admitted to the emergency department with suspicion of CBDS were categorized into either high-risk or non-high-risk groups, on the basis of clinical, biochemical, or transabdominal ultrasound ndings. Patients in the non-high-risk group were randomized to receive EUS plus ERC in one single or in two separate sessions. Results: Eighty patients were recruited and randomized. Forty patients underwent EUS plus ERC in a single session and 40 patients underwent EUS plus ERC in two separate sessions. Negative EUS examination for CBDS avoided unnecessary ERC to 33 patients. Out of 47 patients with positive EUS (25 from the single session group and 22 from the double session), ERC conrmed the presence of CBDS in 46 cases (EUS sensitivity 100% and specicity 98%). Average time of procedure and hospitalization were signicantly shorter in the single session group compared to the two session group. The single session strategy was also less expensive. Conclusion: Endoscopic ultrasonography plus ERC with sphincterotomy and stone extraction performed during the same endoscopic session was safe and efcacious with a reduction of procedure time, hospitalization and costs.

Introduction
Common bile duct stones (CBDS) occur in up to 20% of patients with gallbladder stones,1 and may be associated with severe complications, such as pancreatitis and cholangitis.2,3 Over the last three decades, endoscopic retrograde cholangiography (ERC) has been the primary technique used for the diagnoses and treatment of many pancreatic and biliary diseases; the sensitivity and the specicity of ERC for detection of CBDS4 are of 90% and of 98%, respectively. Furthermore, this technique allows not only detection but also extraction of the stone during the same endoscopic session. However, the procedure can be

associated with an overall complication rate of 510% and a mortality rate of 0.020.5%.58 Thus, non-invasive diagnostic tests are previously performed to select patients with suspected CBDS for ERC. Based on clinical and biochemical criteria, together with transabdominal ultrasonography (TUS) ndings, patients can be classied into low, intermediate, moderate and high risk for choledocholithiasis,9 however, these criteria are neither highly sensitive nor specic.10 Endoscopic ultrasonography (EUS) is a less invasive techique11 compared to ERC, with excellent overall sensitivity and specicity for diagnosing choledocholithiasis; therefore, EUS should be used
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to select patients that require therapeutic ERC, in order to minimize the risk of complications associated with unnecessary diagnostic ERCs, as well as a considerable economic advantage by preventing inappropriate and more invasive procedures.12 Furthermore, EUS-guided management algorithm could be cost-effective in patients with a low to a moderate risk of biliary obstruction, while in high-risk patients the ERC-guided approach may be more cost-saving since most of these patients would require ERC intervention anyway.9,1315 In case of suspected CBDS or biliary sludge it has been suggested to perform EUS plus ERC during the same endoscopic session,16,17 however, the real advantages of this approach have yet to be demonstrated. The aim of this randomized trial is to compare in patients with suspected CBDS the clinical and economic impact of EUS plus ERC performed during a single endoscopic session (one step) versus EUS plus ERC during two separate sessions (double step).

Methods
All adult patients admitted to the emergency department with suspicion of biliary stone disease on the basis of clinical, biochemical or TUS ndings were evaluated. The inclusion criteria for the study were: 1 Presence of biliary-type colicky pain. 2 Levels of serum bilirubin and/or alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) more than twice the upper normal limit. 3 TUS evidence of gallbladder stones with normal or initial dilatation of common bile duct (710 mm) and no evidence of CBDS. The exclusion criteria were: 1 History of previous cholecystectomy, choledochojejunostomy, gastrectomy and sphincterotomy. 2 Patients with acute cholangitis and/or pancreatitis. 3 Patients with a denite TUS diagnosis of CBDS, isolated intrahepatic ductal dilation or with suspected biliary stricture due to biliary or pancreatic malignancy. 4 Patients hemodynamically unstable or with severe coagulopathy (international normalized ratio [INR] > 1.5 or platelet count < 50 000 cells/cubic millimetre [cmm3]). 5 Age less than 18 years. 6 Pregnancy. 7 Inability or refusal to give informed consent. 8 Refusal to participate to the study. Randomization of patients in EUS plus ERC single step group or double step group was carried out by a computer-generated list. Assignments were prepared in a 1 : 1 proportion and the allocation was concealed using an opaque envelope system. All procedures were performed by a team composed by two endoscopists (an endosonographer and a biliary endoscopist), one anaesthesiologist and two nurses. Endoscopic ultrasonography was performed using a linear echo-endoscope (Fujinon, Inc., Saitama, Japan) at 5.0 or 10 MHz frequency by an experienced echo-endoscopist (C.F.) who had previously received formal fellowship training in diagnostic and therapeutic EUS, with a current case volume of 450 per year.
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Endoscopic retrograde cholangiography, sphincterotomy, precut if necessary, and extraction of stones and/or sludge were performed with a video duodenoscope (Fujinon, Inc.) by two endoscopists who have respectively 10 (V.C.) and 30 (N.D.) years of experience, with an ongoing workload of > 250 ERCPs/year. An anesthetist performed deep sedation with intravenous propofol. Patients received a starting dose of intravenous propofol of 0.5 mg/Kg, followed by a continuous infusion during all the procedure using a medical pump at an initial rate of 0.05 mg/Kg per minute. All patients also received oxygen through a nasal tube and were monitored with pulse oxymeter, three lead electrocardiograph and automated blood pressure cuff. Heart rate, mean arterial pressure and oxygen saturation were measured before sedation and during all the procedure. The duration of the procedures, from the propofol infusion to the withdrawal of the endoscope, were recorded. Endoscopic ultrasonography was considered positive if there was a reproducible hyperechoic focus with or without associated acoustic shadowing or if there was biliary sludge obstructing the common bile duct. A positive EUS result was considered a true positive only if the stones or the sludge were conrmed by ERC, sphincterotomy and basket or balloon sweep. In the single step group, the CBDS detected with EUS were immediately removed by ERC during the same session. It must be emphasized that ERC for CBD clearance was done immediately after EUS, in the same room, under the same anesthesia, by retrieving the echo-endoscope and introducing a duodenoscope; furthermore, sphincterotomy was always followed by Dormia basket and balloon catheter exploration of the bile ducts. In the double step group, the CBDS detected with EUS were removed two or three days later, during a separate session. If no CBDS were found on EUS, ERC was not performed and patients were followed-up for twelve months in order to exclude false-negative diagnosis. The follow-up included clinical, biochemical and TUS data at 3, 6 and 12 months. All patients were scheduled for elective cholecystectomy. Written informed consent for the procedures performed and for the participation in the study was obtained from all patients and the ethics committee of our institution approved the study protocol. The primary end point of the study was to evaluate the clinical impact of the EUS plus ERC single step strategy in terms of procedural time and days of hospitalization in comparison to EUS plus ERC double step strategy; the accuracy of EUS for CBDS and the number of ERCs avoided was also evaluated. The secondary end point was to evaluate the economic impact of EUS plus ERC in a single endoscopic session versus EUS plus ERC in two separate sessions.

Economic and statistical analysis

The variables evaluated were: Age, sex, serum bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, alanine-amino transferase, aspartate aminotransferase, diameter of bile duct at TUS, propofol dosage, duration of procedure, hospitalization days and costs of the two strategies. The cost estimates included, hospitalization costs, direct procedure costs of EUS and ERC, and indirect costs such as patient monitoring, intravenous kits and drugs, laboratory tests,

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endoscopists and anesthetists fees, nurse fee, endoscopy room time, uoroscopy and all non-reusable endoscopic equipment. The numerical data are expressed as mean, standard deviations and range, while the categorical variables are reported as numbers and percentages. Examined variables did not present normal distribution as veried by Kolmogorov Smirnov test,18 therefore, the non-parametric approach has been used. In order to compare the two groups of patients (single session vs double session) for each variable, we applied the non parametric combination (NPC) test,19 this method allows investigation of the directionality of the comparison, verifying alternative directional hypotheses. Values of P < 0.05 were considered statistically signicant. Diagnostic tests for sensibility, specicity, positive predictive value and negative predictive value have been performed to evaluate the accuracy of EUS.20 The software used for the analyses were: SPSS Windows 11.0 (2001, SPSS Inc., Chicago, IL, USA) for descriptive statistics, Methodologica S.R.L. (2001, Methodologica S.R.L, Treviso, Italy) for NPC Test; CIA (Timberlake Consultants LTD, London, UK) for sensibility and specicity calculation.

Results
During an 11-month period, from June 2006 to May 2007, 138 patients admitted at our emergency department with suspicion of biliary stone disease were evaluated. Fifty-eight patients (42%) did not meet inclusion criteria and were excluded (42 patients with an high risk for CBDS, 12 patients with previous cholecystectomy, 1 patient with previous gastrectomy and 3 patients with advanced liver cirrhosis and coagulopathy), while 80 patients were recruited into the study (Fig. 1). The demographic, clinical and biochemical characteristics of the study population are shown in Table 1. According to risk stratication9 based on clinical, biochemical and TUS criteria, 18 patients (22.5%) had a low risk for CBDS, 35 patients (43.8%) had an intermediate risk and 27 patients (33.7%) had a moderate risk. All patients were randomly assigned to the two strategy groups; therefore, 40 patients were allocated in the EUS plus ERC single session group and 40 in the double session group. No signicant differences regarding sex, age, bile duct diameter at TUS, levels of

Figure 1

Flow chart of selection and randomization of patients.

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Table 1 Demographic, clinical and biochemical characteristics of the study population Number Age Sex (M/F) AST(U/L) ALT(U/L) GGT(U/L) AP (U/L) Bilirubin (mg/dL) Bile duct diameter (TUS mm) 80 61.7 17.3 39/41 122.5 104.5 178.1 145.3 181.2 122.4 551.3 293.4 2.2 1.6 6.9 1.3

AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma glutamyl transpeptidase; AP, alkaline phosphatase; TUS, transabdominal ultrasonography.

Table 2 P values relative to comparison of two groups randomized (NPC test) One step N: 25 Age Sex (M/F) AST (U/L) ALT (U/L) GGT (U/L) AP (U/L) Bilirubin (mg/dL) Bile duct diameter (TUS mm) Duration of procedure (min) Propofol dosage (mg) Hospitalization days Hospitalization costs () Total costs () 63 19 11/14 155.8 131.1 215.1 179.6 213.6 152.4 575 308.4 2.6 1.9 6.9 1.4 59.3 8.9 232.5 64.1 5 0.8 2192.4 343.4 3474.3 343.4 Double step N: 22 58 15.1 10/12 115.3 84.8 167.1 102.1 169.4 110 558.7 285.8 2 1.2 7 1.3 87.4 7.2 348.5 73.1 7.5 0.9 3282.3 396.6 4771.2 785.4 P value

0.329 0.955 0.215 0.282 0.266 0.524 0.275 0.425 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

All stones and sludge were removed after sphincterotomy with basket or balloon and. Precut was performed in 12 patients (6 in the single session and 6 in the double session group). We observed only one complication related to the procedures that occurred to a patient of the single session group, who developed a mild post-ERC pancreatitis, resolved with conservative treatment. No complications related to sedation or EUS were observed. All patients underwent cholecystectomy in the 12 months follow-up period, as did the 33 patients that did not undergo ERC, since none of them presented signs of biliary disease during the follow-up period. The sensitivity, specicity, positive and negative predictive values of EUS for the diagnosis of CBDS or sludge were 100%, 98%, 100% and 98%, respectively, with one false positive case. Furthermore, the ERCs avoided after EUS was performed were 33 out of 80 cases (41.2%). The average procedure time was signicantly shorter in the single session group (59.3 8.9 min, range 4590) compared to the double session group (87.4 7.2 min, range 78105) (P < 0.001). The propofol dosage administered during each procedure in the single session group (232.5 64.1 mg, range 125375) was remarkably lower than the dosage required in the double session group (348.5 73.1 mg, range 235500) (P < 0.001). Furthermore, days of hospitalization were signicantly less in the single session group (5 0.8 days, range 48) compared to the double step group (7.5 0.9 days, range 610) (P < 0.001). The rate of hospitalization of the two strategies expressed in Euros () was signicantly less costly (P < 0.001) in the single session group (2192.4 343.4, range 17403480 vs 3282.3 396.6, range 26104350). Finally, the total costs of the single session (3474.3 343.4 Euros, range 3021.944761.94) was signicantly lower (P < 0.001) compared to the double session (4771.2 785.4 Euros, range 4099.055836.05).

Discussion
Endoscopic retrograde cholangiography is considered the gold standard for diagnosing choledocholithiasis; however, this technique is not free from risk and complication rates doubles when sphincterotomy is also performed.6,21 Endoscopic ultrasonography is a minimally invasive procedure with morbidity and mortality rates similar to conventional endoscopy.22 Endoscopic ultrasonography showed to be the best diagnostic test in patients at risk of CBDS, with an excellent overall accuracy. Thus EUS should be used to select which patients should undergo therapeutic ERC. Furthermore, EUS-based strategy with selective therapeutic ERC can reduce of 6075% the number of diagnostic ERC performed in patients who are at non-high-risk for choledocholithiasis.2325 In our study, prior EUS evaluation avoided unnecessary ERC procedures in 33 patients (41.2%); indeed, during follow-up period none of these patients presented any biliary complications and all of them underwent regular cholecystectomy. Our results are similar to previous prospective study by Berdah et al.; in this trial no long-term sequelae were observed during a 2-year follow-up of patients with a negative EUS, performed before undergoing cholecystectomy.26

AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma glutamyl transpeptidase; AP, alkaline phosphatase; TUS, transabdominal ultrasonography.

alanine-amino transferase, aspartate aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatase, and serum bilirubin were observed in the two groups (Table 2). A complete view of extra hepatic biliary tree and of gallbladder was obtained by EUS in all patients. Gallbladder stones were conrmed in all patients. After EUS examination, 47 patients were positive for CBDS (37 cases) or sludge (10 cases), while in 33 patients (41.2%) no CBDS or sludge were found, therefore, they did not undergo ERC but were followed-up and scheduled for cholecystectomy. Of the 47 patients (7 low risk, 20 intermediate risk and 20 moderate risk) with a positive EUS, 25 patients (4 low risk, 11 intermediate risk and 10 moderate risk) belonged to the single session group and 22 (3 low risk, 9 intermediate risk and 10 moderate risk) to the double session group. Furthermore, out of the ten cases of biliary sludge and the 37 of CBDS, forty-six (98%) were conrmed at ERC.
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Furthermore, a recent meta-analysis by Tse et al. showed that EUS had a high overall pooled sensitivity of 94% (95% CI, 0.93 0.96) and a specicity of 95% (95% CI, 0.940.96) for the detection of choledocholithiasis.11 Similarly, in our study, EUS has a very high sensitivity (100%) and specicity (98%) with a positive predictive value of 100% for detecting CBDS and sludge, with only one false positive case. The rapidly developing medical technologies continuously offer new and often expensive diagnostic and therapeutic options, while having to face a constant reduction of nancial resources of health insurance services. Thus, due to these limited resources, expensive technologies should be used rationally and only when they are very likely to improve patients care rather than be used indiscriminately. Prat et al. suggested that CBDS found during EUS examination should be treated and extracted in the same endoscopic session with ERC and sphincterotomy, ideally performed immediately after EUS with no interruption of sedation.16 In addition, single session strategy allows reduction of costs and time of treatment, aimed at offering patients an optimal combination of currently available therapeutic techniques and also to reduce the discomfort and risk through a shorter time of sedation and less endoscopic intubations. Indeed, even in experienced hands, ERC failure rate is 510%,27 and in these cases the examination may need to be repeated, increasing the number of endoscopic procedures and sedations; such an event may occur more often when an aggressive technique such as precut papillotomy is used for cannulation. Furthermore, the single session procedure may not be performed in patients with primary or secondary coagulation disorders, such as patients with liver cirrhosis or taking anticoagulant drugs, because ERCP is considered to be a high risk procedure in these conditions. Thus, EUS should be used on its own to conrm the presence of CBDS or sludge, while ERCP should be performed in a separate session in order to reduce risk for these patients. This is the rst known randomized study that compares EUS plus ERC during the same endoscopic session and EUS plus ERC in two separate sessions for the management of choledocholithiasis. Our results show that average procedure time (P < 0.001) and days of hospitalization (P < 0.001) were signicantly reduced in the single session group compared to the double session group, resulting in signicant differences also in terms of hospitalization rate (P < 0.001) and total costs (P < 0.001). Limitations of the current study are the small numbers of patients included, the single-centre design and its reproducibility and diffusion. Indeed, there are some challenges when performing EUS plus ERC at the same session, such as having the EUS and the ERC equipment, with uoroscopy, in the same room, as well as having two physicians that will perform EUS and ERC available at the same time. These problems can be overcome by building big interventional endoscopic rooms where it is possible to allocate both the EUS and the ERC equipments, and by training pancreaticobiliary endoscopists to be competent in both ERC and EUS techniques. Indeed, as emphasized in a recent editorial by Savides,28 the biliary interventional endoscopists of the future should be able to use EUS to distinguish between a stone and a mass, and also be

able to perform a basic ERC with biliary sphincterotomy and stone extraction or biliary stent placement. In conclusion, our data suggest that EUS should be used to select patients with non-high-risk for CBDS that should undergo ERC to avoid performing unnecessary ERCs. Furthermore, if stones are detected during EUS, ERC with sphincterotomy and extraction should be performed in the same endoscopic session, reducing costs and time of the procedures as well as discomfort and risks for patients. However, further large prospective randomized studies that compare single session EUS plus ERC versus double session for choledocholithiasis are needed to conrm our data.

Conict of interest
There are no nancial arrangements or commercial associations (e.g. equity ownership or interest, consultancy, patent and licensing agreement, or institutional and corporate associations) that might be a conict of interest in relation to the submitted manuscript.

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