Randomized trial comparing needle-knife and pull-sphincterotome techniques for pancreatic sphincterotomy in high-risk patients

ORIGINAL ARTICLE: Clinical Endoscopy

Randomized trial comparing needle-knife and pull-sphincterotome techniques for pancreatic sphincterotomy in high-risk patients Shyam Varadarajulu, MD, C. Mel Wilcox, MD Birmingham, Alabama, USA

Background: Accepted techniques for pancreatic sphincterotomy include use of a needle knife or a pull sphincterotome to ablate the sphincter. There are no prospective studies comparing outcomes between both techniques. Aim: Compare post–ERCP pancreatitis rates among high-risk patients undergoing pancreatic sphincterotomy with the pull-sphincterotome versus needle-knife technique. Study Design: Prospective, randomized trial. Methods: Patients diagnosed with pancreatic sphincter hypertension at sphincter of Oddi manometry were randomized to undergo pancreatic sphincterotomy with a pull sphincterotome (followed by pancreatic stenting) or a needle knife over a pancreatic stent. Main Outcome Measurements: To compare post-ERCP pancreatitis rates between the pull-sphincterotome and needle-knife groups. Results: Forty-eight patients were randomized. Patient demographics and the incidence of patient and procedure risk factors for pancreatitis were similar in both treatment groups. The trial was stopped early after an interim analysis showed that post-ERCP pancreatitis was significantly higher among patients undergoing sphincterotomy with a pull sphincterotome than a needle knife (7/24 Z 29% [95% CI 13-51] vs 0/24 Z 0% [95% CI 0-12]; P Z .01). No other complications were encountered. At a mean follow-up of 12 months (range 6-18 months), 60% of patients had complete symptom relief, 15% partial symptom relief, and 25% recurrent symptoms. Reintervention rates and clinical outcomes were not significantly different between the 2 groups. Limitations: Short duration of follow-up. Conclusions: Pancreatic sphincterotomy is safer in high-risk patients when performed with a needle knife over a pancreatic stent. (Gastrointest Endosc 2006;64:716-22.)

Copyright ª 2006 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2006.02.058

the only large multivariate study in which it was evaluated.7 The risk of post–ERCP pancreatitis is determined by the characteristics of the patient as well as by endoscopic techniques or maneuvers.9 The rate of post-ERCP pancreatitis is much higher in patients with a healthy pancreas, such as patients with sphincter of Oddi dysfunction (SOD), than those with a diseased gland, such as in chronic pancreatitis.2,3,10 With regard to technique, there are 2 standard methods for performing pancreatic sphincterotomy: one involves placement of a standard pull-type sphincterotome in the pancreatic duct oriented along the axis of the pancreatic duct and an incision is made, and the other involves using a needle-knife to perform the sphincterotomy over a previously placed pancreatic stent. From available data, it is difficult to determine the relative safety of one

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Endoscopic pancreatic sphincterotomy (EPS) was first described in detail by Fuji et al1 in 1985. The technique has not been widely practiced because of a lack of welldefined criteria for its use. In most studies in which it has been used, EPS was performed as an adjunctive therapy to allow access to the pancreatic duct for other maneuvers, such as removal of pancreatic stones, stent placement, and pseudocyst drainage.2-6 Although performance of biliary sphincterotomy does not appear to add a significant independent risk of pancreatitis,7,8 EPS, on the other hand, was found to be a significant risk factor for pancreatitis in

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Randomized trial comparing needle-knife and pull-sphincterotome techniques

technique over the other.11-15 EPS in most of these patients was performed as an adjunctive to other therapies; hence, the frequency of complications directly attributable to EPS alone is difficult to interpret. Subjects with SOD represent a ‘‘vulnerable’’ cohort with a high rate of complications after pancreatic endotherapy.10 Although placement of prophylactic pancreatic stents has significantly decreased post-ERCP pancreatitis rates in this patient population,16,17 other measures to minimize complication risks require evaluation. Although most experts perform EPS with either a pull-sphincterotome or a needle knife, the relative safety of one technique over the other is yet to be determined. To address this issue, we conducted a prospective randomized trial of all patients with SOD who underwent EPS with the needle-knife and pull-sphincterotome techniques.

Capsule Summary What is already known on this topic d

The rate of post-ERCP pancreatitis is much higher in patients with SOD.

What this study adds to our knowledge d

In a prospective, randomized trial of 48 patients with SOD who underwent endoscopic pancreatic sphincterotomy, post-ERCP pancreatitis was significantly higher in the pull-sphincterotome group (7/24, 29%) than in the needle-knife group (0/24).

Endoscopic SOM was performed with the patient under conscious sedation with intravenously administered midazolam and meperidine in all patients. The use of drugs that affect sphincter of Oddi motility, such as anticholinergic or calcium-channel blocking agents, was avoided for 24 hours before the procedure. Glucagon, to control duodenal contractility, was not administered until completion of the manometry. All procedures were performed by one of 2 endoscopists with more than 5 years’ experience (O300 ERCPs/y). SOM was performed with a pneumohydraulic triple-lumen catheter (WilsonCook Medical, Winston-Salem, NC) with a diameter of 1.7 mm and 3 recording side ports. A low compliance pump (Arndorfer Medical Specialists, Greensdale, Wis)

was used to perfuse 2 catheter lumens with water at a rate of 0.25 mL per minute. Pressures were recorded with a multichannel instrument. After duodenal pressure was recorded, the catheter was advanced freely into the pancreatic duct or the common bile duct. The duct entered was identified by gentle aspiration through any port. The appearance of yellow-colored fluid in the endoscopic view was taken to indicate entry into the bile duct; a clear aspirate was taken to indicate pancreatic duct entry. Pressure recordings were made while the catheter was pulled through the sphincter of Oddi in a stepwise fashion. Continuous aspiration was performed with use of the third port of the manometry catheter while in the pancreatic duct. SOD was defined as a basal pressure greater than or equal to 40 mm Hg in both leads. Any abnormal basal sphincter pressures sustained for at least 30 seconds in each lead was confirmed on 2 or more separate pullthroughs. Although amplitude, frequency, and sequences of phasic waves were determined, these were not used as criteria for determining whether the test results were normal or abnormal. Retrograde cholangiopancreatography was performed in all patients after manometry. A maximum of 8 cannulation attempts was permitted with the manometry catheter. If deep cannulation was not attained in 8 attempts, the ducts were cannulated with use of a sphincterotome and a 0.18-inch guidewire (Glidewire; Boston Scientific, Watertown, Mass). After the guidewire was deep within the ductal system, it was exchanged for a manometry catheter. However, patients in whom the initial cannulation failed by use of a manometry catheter were excluded from the study because multiple cannulation attempts have been shown to be an independent risk factor for post-ERCP pancreatitis.10 At ERCP, if PSH was diagnosed at SOM, an endoscopy nurse opened a sealed envelope that contained computer-generated randomization assignments. Patients were randomized to undergo EPS with a needle knife or a pull sphincterotome. Patients with recurrent pancreatitis who had elevated basal sphincter pressures in the pancreatic segment of the sphincter of Oddi underwent EPS. If the pancreatic

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PATIENTS AND METHODS Patients Consecutive patients 18 years of age or older who underwent sphincter of Oddi manometry (SOM) for evaluation of suspected SOD were eligible for participation in the study. Only those patients diagnosed with pancreatic sphincter hypertension (PSH) and treated with EPS were included in the study. Patients with any previous endoscopic or surgical intervention involving the major duodenal papilla or history of upper GI surgery with altered digestive tract anatomy were excluded. Patients who underwent EPS despite normal SOM findings and those who underwent only biliary sphincterotomy as treatment for PSH were also excluded. Patients in whom the pancreatic duct could not be cannulated by the manometry catheter within 8 attempts and those in whom prophylactic pancreatic stents were not placed after EPS were excluded from the study. All participating patients provided informed consent. The study was approved by the institutional review board of our medical university.

Procedures

Randomized trial comparing needle-knife and pull-sphincterotome techniques

Figure 1. Pancreatic sphincterotomy performed with a pull sphincterotome with the axis oriented toward the 1 o’clock position (A) followed by placement of a 3F prophylactic pancreatic stent (B).

segment pressures were normal, then the biliary sphincter was evaluated, and a biliary sphincterotomy was performed if the pressures were elevated. Patients with postcholecystectomy pain underwent sphincter ablation on the basis of manometry readings. If basal pressures were elevated in both segments of the sphincter, a dual sphincterotomy was performed at the same setting. If pressures were elevated in only 1 segment of the sphincter of Oddi, then the corresponding sphincter was ablated. Patients in whom EPS was not done were excluded from the study. Technique of pancreatic sphincterotomy. In patients randomized to the pull-sphincterotome wing, the initial cannulation was performed with a 4.5F pull-type sphincterotome (Apollo, CONMED Endoscopic Technologies, Billerica, Mass) loaded with a 0.018-inch hydrophilic wire (Glidewire; Boston Scientific). Once the wire was advanced well into the pancreatic duct and deep cannulation was achieved, EPS was carried out in the direction from 718 GASTROINTESTINAL ENDOSCOPY Volume 64, No. 5 : 2006

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the 1 o’clock to the 2 o’clock position with 40 W of blended cutting current (Fig. 1A and B). An effort was made to maximize the size of the sphincterotomy; the maximum size was considered to have been reached when increased resistance to further progress of the cutting wire was noted. The incision length was estimated by pull through of an open sphincterotome. After EPS, a 3F unflanged pigtail pancreatic stent (8, 10, or 12 cm in length) was placed. In others, EPS was performed with a needle-knife (Huibregtse single-lumen needle knife, Wilson-Cook Medical) over a 3F (8, 10, or 12 cm in length) unflanged pigtail plastic stent (Wilson-Cook Medical) (Fig. 2A and B). Needle-knife sphincterotomy was performed with 40 W of blended current. The stent acted as a guide and the sphincter was unroofed over the stent with a needle-knife. The incision length was estimated by the ability to cannulate the pancreatic duct freely by the side of the stent with the needle-knife sphincterotome (after retracting the needle once sphincterotomy was completed). An abdominal flat-plate x-ray film was obtained after 3 weeks to confirm spontaneous stent passage. If the stents were still in place, they were retrieved endoscopically by referring gastroenterologists. All patients were contacted by an endoscopy nurse at 48 hours to check for postERCP complications that were assessed according to consensus criteria.18 The nurse was not aware of the randomization assessment. Referring physicians and patients were contacted to obtain follow-up information regarding responses to endoscopic interventions at 3-month intervals for 1 year. Study outcomes. The primary outcome evaluated was rates of post-ERCP pancreatitis between patients randomized to the pull-sphincterotome and needle-knife groups. We also collected data on endoscopic reintervention and provided clinical follow-up on both groups of patients.

Statistical analysis Continuous variables were reported as mean (SD) and median (range). Categorical variables were reported as frequencies with respective percentages. Outcome of interest was presence or absence of post-ERCP pancreatitis. With P1 (proportion of subjects with post-ERCP pancreatitis in procedures where needle knife was used) equal to 0.10 and P2 (proportion of subjects with post-ERCP pancreatitis in procedures where sphincterotome was used) equal to 0.30, the sample size required (using Fisher exact 2-sided test) to detect a statistically significant difference (a Z .05) was 142 (71 in each group) with 80% power. An interim analysis was planned when approximately one third of the total enrollment population was enrolled. A P value of !.02 for rate of post-ERCP pancreatitis (the primary outcome) was preselected for significance for the interim analyses and for stopping the study early. For the final analysis, a P value of !.05 for the primary www.giejournal.org

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Randomized trial comparing needle-knife and pull-sphincterotome techniques

outcome (post-ERCP pancreatitis rate) was chosen at the study onset as statistically significant.

RESULTS Between June 2004 and August 2005, 78 patients were referred for SOM. Thirty patients were excluded from the study. The reasons for exclusion were prior endoscopic interventions of the major duodenal papilla in 9 patients, technical inability to cannulate the pancreatic duct initially using a manometry catheter (4 patients), normal SOM study results (8 patients), isolated biliary sphincter hypertension managed by biliary sphincterotomy (8 patients), and failure to perform EPS as a result of difficult ductal anatomy despite documented PSH at SOM (1 patient). The other 48 patients were diagnosed with PSH by SOM and were randomized to undergo EPS by the needle-knife technique (n Z 24) or the pull-sphincterotome technique (n Z 24). We successfully placed 3F prophylactic pancreatic stents in all 48 patients. Randomization of patients into this study was stopped before all the planned enrollment was completed because the interim analysis showed a significant difference in the primary end point: post-ERCP pancreatitis rates. This end point was considered to be clinically relevant. On the basis of these significant differences in the primary outcome, the study was stopped and a follow-up of all randomized patients was conducted. At baseline (randomization), the 2 groups of randomized patients were well matched with respect to demographics, procedural indications, and disease classification (Table 1). Two patients randomized to the pull- sphincterotome wing and three in the needle-knife wing had mild pancreatitis on pancreatogram by Cambridge criteria. The proportion of patients undergoing EPS per se or dual sphincterotomy was equally distributed between both groups. Procedural times were not significantly different between both groups of patients (Table 1).

different between the two participating endoscopists: 4 versus 3.

Post-ERCP pancreatitis

Reintervention rates

Although no patient randomized to the needle-knife wing had post-ERCP pancreatitis, 7 had post-ERCP pancreatitis in the pull-sphincterotome wing, of which 3 cases were of moderate severity (0/24 Z 0% [95% CI 0-12] vs 7/24 Z 29.2% [95% CI 13-51], P Z.01) (Table 1). Although all subjects in whom pancreatitis developed were managed as inpatients, those with a moderate attack required prolonged hospitalization (mean 6 days, range 5-9 days). All patients were managed conservatively without the need for surgery or blood transfusions. Two of 3 patients with moderate pancreatitis were administered intravenous antibiotics for persistent fever and leukocytosis despite negative blood cultures. No complications other than pancreatitis were encountered in this study. The rate of post-ERCP pancreatitis in this study was not significantly

There were no significant differences in reintervention rates between the groups (Table 1). At a mean short-term follow-up of 12 months, 3 in the sphincterotome wing and 2 in the needle-knife wing underwent repeat manometry for evaluation of persistent symptoms. Two of 3 patients in the pull-sphincterotome group and 1 in the needleknife group had normal SOM readings on repeat ERCP and were managed conservatively. One patient in the needle-knife group who previously was managed with EPS for complaints of abdominal pain underwent biliary sphincterotomy because of high basal sphincter pressures; his pancreatic sphincter pressures were !20 mm Hg. One patient in the sphincterotome wing who previously was managed with biductal sphincterotomy for complaints of abdominal pain had elevated pancreatic basal sphincter

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Figure 2. Pancreatic sphincterotomy performed with a needle-knife sphincterotome over a 3F pancreatic stent (A) followed by free cannulation of the pancreatic duct (B).

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TABLE 1. Characteristics and outcomes in patients undergoing pancreatic sphincterotomy Sphincterotomy technique Characteristic

Pull sphincterotome (n Z 24) (No. [%])

Needle knife (n Z 48) (No. [%])

P value

Total

Age (y) Mean (SD) Median (range) Women

46.3 (15.8)

45.4 (15.1)

48 (18-72)

.84*

42.5 (19-82)

45.9 (15.3) 47 (18-82)

18 (75.0)

21 (87.5)

.46y

5 (20.8)

10 (41.7)

.21y

Pancreatitis

19 (79.2)

14 (58.3)

Cholecystectomy

14 (58.3)

18 (75.0)

.36y

32 (66.7)

Biliary I

d

d

d

d

Biliary II

d

3 (12.5)

.23y

3 (6.2)

Biliary III

3 (12.5)

4 (16.7)

1.00y

7 (14.6)

Pancreatic I

d

d

d

d

Pancreatic II

17 (70.8)

11 (45.8)

.14y

28 (58.3)

Pancreatic III

4 (16.7)

6 (25.0)

.72y

10 (20.8)

Dual sphincterotomy

8 (33.3)

14 (58.3)

.15y

22 (45.8)

Mean (SD)

61.0 (14.8)

63.9 (16.0)

.52*

62.5 (15.3)

Median (range)

60.5 (32-110)

63.5 (35-105)

Reinterventions

3 (12.5)

2 (8.3)

.70y

8 (16.7)

Pancreatitis

7 (29.2)

0

.01y

7 (14.6)

Mild

4 (57.1)z

d

4 (57.1)

Moderate

3 (42.9)z

d

3 (42.9)

d

d

d

Presenting complaints Pain

15 (31.2) 33 (68.8)

SOD types

Procedural time (min)

Severe

61 (32-110)

Relief from symptomsx Complete

13 (54.2)

15 (62.5)

Partial

7 (29.1)

5 (20.8)

.77y

12 (25.0)

28 (58.3)

Recurrence

4 (16.7)

4 (16.7)

8 (16.7)

*Unpaired Student 2-tailed t test. yFisher 2-tailed exact test. zPercentage calculated out of the ‘‘total’’ pancreatitis. xTo calculate, partial relief and recurrence of symptoms categories are combined.

pressures at repeat ERCP, which was managed by EPS with the needle-knife technique.

There were no significant differences in clinical outcomes between groups (Table 1). At short-term follow-up

(mean 12 months, range 6-18 months), 28 patients had complete symptom relief (58%), 12 had partial symptom relief (25%) and 8 had persistent symptoms (17%). Patients were queried over telephone on their clinical response to treatment. No objective questionnaires were used to evaluate quality of life or clinical response to treatment.

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Clinical follow-up

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Randomized trial comparing needle-knife and pull-sphincterotome techniques

DISCUSSION There are no prior prospective studies that have compared outcomes between the 2 techniques of pancreatic sphincterotomy. In this prospective study of high-risk patients, pancreatic sphincterotomy performed with a pull sphincterotome resulted in significantly more complications despite placement of prophylactic pancreatic stents in all patients. EPS has previously been evaluated only in the context of adjunctive therapy, resulting in difficulty with interpretation of data because complications encountered cannot be attributed to sphincterotomy alone.11-15 Although patients with SOD comprise a vulnerable cohort, they are most apt for evaluating outcomes of EPS because no other concomitant endotherapy is undertaken except for placement of prophylactic pancreatic stents. We deployed 3F unflanged pigtail stents in all patients; stents placed were 8 cm or longer because shorter stents tend to dislodge sooner. We have previously shown in a large multicenter study that use of small-caliber stents resulted in lower post-ERCP pancreatitis rates in patients undergoing SOM.18 Hence, it is unlikely that stent placement contributed to pancreatitis in any of our patients. The reason for a higher frequency of post-ERCP pancreatitis, despite pancreatic stenting, in patients undergoing EPS with the pull sphincterotome is unclear. We hypothesize that the cutting wire tends to inadvertently injure the juxtapapillary portion of the pancreatic duct, leading to a cascade of events that culminates in pancreatitis, which probably is more severe in patients with a healthy gland. This could be the reason for the insignificant difference in complication rates in other studies that have evaluated a more heterogeneous group of patients.11-15 Another explanation could be that the placement of a pancreatic stent before sphincterotomy facilitates immediate ductal drainage. A thermal injury may not incite so severe an inflammatory reaction in a decompressed duct compared with one caused by a sphincterotome in a patient with a hypertensive sphincter. This study has several limitations. First, placement of pancreatic stents for prophylaxis against post-ERCP pancreatitis could by itself incite pancreatitis. However, given the vulnerability of the cohort studied, not placing a stent would be unethical given the proven advantages with its use. Also, because all patients underwent pancreatic stenting, they by themselves serve as controls and hence were less likely to influence the study findings. Second, given the lack of anatomic landmarks to indicate the maximum extent of a pancreatic sphincterotomy, determining the optimal length is often difficult. The risk of limiting the size of a sphincterotomy is later stenosis of the opening because of incomplete sectioning of the sphincter muscle. The short duration of follow-up in this study might have precluded our ability to evaluate such long-term effects.

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However, the rate of reinterventions and clinical outcomes in both cohorts appeared similar in short-tomedium term follow-up. Third, we did not assess for stent-induced ductal damages by follow-up ERCP. Fourth, the optimal therapy for SOD is yet to be determined. A retrospective study determined that in patients with abdominal pain, dual sphincterotomy provides better outcomes than EPS.19 However, these results have not been validated by prospective studies. In summary, the relative safety of pancreatic sphincterotomy techniques has not been previously evaluated. In this prospective study, we have shown that pancreatic sphincterotomy is safer in high-risk patients when performed with a needle knife over a pancreatic stent.

DISCLOSURE The authors have no disclosures to make.

REFERENCES 1. Fuji T, Amano H, Harima K, et al. Pancreatic sphincterotomy and pancreatic endoprosthesis. Endoscopy 1985;17:69-72. 2. Ashby K, Lo SK. The role of pancreatic stenting in obstructive ductal disorders other than pancreas divisum. Gastrointest Endosc 1995;42: 306-11. 3. Dumonceau JM, Devie`re J, Le Moine O, et al. Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: longterm results. Gastrointest Endosc 1996;43:547-55. 4. Cremer M, Devie`re J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium-term follow-up in seventy-six patients. Endoscopy 1991;23:171-6. 5. Kozarek RA, Ball TJ, Patterson DJ. Endoscopic approach to pancreatic duct calculi and obstructive pancreatitis. Am J Gastroenterol 1992;87: 600-3. 6. Catalano MF, Geenen JE, Schmalz MJ, et al. Treatment of pancreatic pseudocysts with ductal communication by transpapillary pancreatic duct endoprosthesis. Gastrointest Endosc 1995;42:214-8. 7. Freeman ML, DiSario JA, Nelson DB, et al. Risk factors for post-ERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc 2001;54:425-34. 8. Masci E, Toti G, Mariani A, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol 2001;96:417-23. 9. Freeman LM. Adverse outcomes of ERCP. Gastrointest Endosc 2002;56(Suppl):S273-82. 10. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996;26:909-18. 11. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic pancreatic duct sphincterotomy: indications, technique, and analysis of results. Gastrointest Endosc 1994;40:592-8. 12. Esber E, Sherman S, Earle D, et al. Complications of major papilla endoscopic pancreatic sphincterotomy: a review of 236 patients [abstract]. Gastrointest Endosc 1996;43:405. 13. Costamagna G, Gabbrielli A, Mutignai M, et al. Endoscopic pancreatic sphincterotomy (EPS): is this a safe procedure? Results in 128 EPS [abstract]. Gastroenterology 1996;110:A383. 14. Soltani S, Lo SK. How safe is endoscopic pancreatic sphincterotomy (PS)? [abstract] Gastrointest Endosc 1996;43:413.

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15. Elton E, Howell DA, Parsons WG, et al. Endoscopic pancreatic sphincterotomy: indications, outcome, and a safe stentless technique. Gastrointest Endosc 1998;47:240-9. 16. Tarnasky PR, Palesch YY, Cunningham JT, et al. Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction. Gastroenterology 1998;115:1518-24. 17. Fogel EL, Varadarajulu S, Sherman S, et al. Prophylactic pancreatic duct stenting in patients with suspected sphincter of Oddi dysfunction but normal sphincter of Oddi manometry [abstract]. Gastrointest Endosc 2003;57:AB88. 18. Cotton PB, Lehmen G, Vennes J, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc 1991;37:383-93.

19. Park SH, Watkins JL, Fogel EL, et al. Long-term outcome of endoscopic dual pancreatobiliary sphincterotomy in patients with manometrydocumented sphincter of Oddi dysfunction and normal pancreatogram. Gastrointest Endosc 2003;57:483-91.

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Received January 6, 2006. Accepted February 25, 2006. Current affiliations: Division of Gastroenterology-Hepatology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama. Reprint requests: Shyam Varadarajulu, MD, Division of GastroenterologyHepatology, University of Alabama at Birmingham Medical Center, 410 LHRB, 1530 3rd Ave S, Birmingham, AL 35294.