A prospective randomized trial of cannulation technique in ERCP: effects on technical success and post-ERCP pancreatitis

• Introduction
• Methods
• Study population and protocol
• Cannulation protocol
• Cannulation technique
• Follow-up
• Statistical methods
• Results
• Post-ERCP pancreatitis
• Discussion
• Conclusion
• References

Background and study aims: Inadvertent injection of contrast agent into the pancreatic duct is believed to be an important contributor to pancreatitis occurring after endoscopic retrograde cholangiopancreatography (post-ERCP pancreatitis, PEP). Our aim was to examine whether primary deep biliary cannulation with a guide wire is associated with a lower rate of PEP than conventional contrast-assisted cannulation.

Patients and methods: From August 2003 to April 2006 all patients with an intact papilla who were referred for ERCP were eligible. Patients with pancreatic or ampullary cancer were excluded. Patients were randomized to undergo sphincterotome biliary cannulation using either contrast injection or a guide wire. The ERCP fellow attempted initially for 5 minutes. If unsuccessful, the consultant attempted for 5 minutes using the same technique, followed by crossover to the other technique in the same sequence and then needle-knife sphincterotomy where appropriate. Patients were assessed clinically after the procedure, then followed up with telephone interviews after 24 hours and 30 days, and serum amylase and lipase tests after 24 hours.

Results: Out of 1654 patients undergoing ERCP, 413 were included in the study. PEP occurred in 29/413 (7.0 %): 16 in the guide-wire arm, 13 in the contrast arm (P = 0.48). The overall cannulation success rate was 97.3 %. Cannulation was successful without crossover in 323/413 patients (78.2 %): 167/202 (81.4 %) in the guide-wire arm and 156/211 (73.9 %) in the contrast arm (P = 0.03). Multivariate analysis demonstrated female sex (OR = 2.7, P = 0.04), suspected sphincter of Oddi dysfunction (OR = 5.5, P = 0.01), and complete filling of the pancreatic duct with contrast agent (OR = 3.5, P = 0.02) to be independently associated with PEP. The risk of PEP increased incrementally with each attempt at the papilla (OR 1.4 per attempt, P = 0.04) to greater than 10 % after four or more attempts.

Conclusions: The guide-wire technique improves the primary success rate for biliary cannulation during ERCP but does not reduce the incidence of PEP compared to the conventional contrast technique. The incidence of PEP increases incrementally with each attempt at the papilla.

Introduction

Since the first descriptions of endoscopic cholangiography in 1968 [1], followed by the first endoscopic sphincterotomy in 1974 [2], endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy has emerged as the definitive procedure for simultaneous diagnosis and treatment of biliary disease. The indications for and therapeutic role of ERCP have expanded considerably to include a diverse array of pancreatic and biliary pathologies [3]. For purely diagnostic purposes, current noninvasive imaging modalities are preferred as ERCP carries an unacceptable incidence of complications in this setting [4] [5].

Despite the widespread dissemination of the practice of ERCP, the procedure remains compounded by two persistent problems: failure of successful biliary cannulation, and post-ERCP pancreatitis (PEP). When performed outside expert, high-volume centers, failure of biliary cannulation may occur in up to 20 % of cases [6] [7] [8], with resultant prolonged attempts at cannulation which enhance the risk of pancreatitis, delay definitive therapy, and necessitate recourse to alternative therapeutic techniques with inferior safety profiles [9]. PEP is the most frequent complication of ERCP. In published series, it occurs at a rate of between 2 % and 40 % [4] [10] [11] [12] [13] [14] [15]. The majority of studies report pancreatitis rates between 5 % and 10 %. Most cases are reported as mild, but pancreatitis can be severe or fatal [4]. The risk of PEP is known to increase with prolonged attempts at cannulation [4] [11] [12].

Cannulation technique is believed to be pivotal in the genesis of PEP and is obviously important for successful cannulation. Cannulation with a sphincterotome appears to be the most efficient technique for biliary access; however, the safest and most effective approach with this device has not been clearly established [16] [17] [18] [19] [20]. By means of a randomized trial, we sought to examine whether either primary guide-wire-assisted cannulation or conventional contrast injection was superior for technical success and/or safety.

Methods

Study population and protocol

All patients with an intact papilla were eligible for the study. Referrals were accrued from local gastroenterologists and surgeons, as well as from other regions and states. Exclusion criteria included the following: age below 18 years, acute illness (hypotension: systolic blood pressure below 90 mm Hg; hypoxia: oxygen saturation less than 95 % on supplemental oxygen; hemodynamic instability), and inability or refusal to give informed consent. Patients with previous sphincterotomy and pancreatic or ampullary cancer were excluded as PEP is very uncommon in these subgroups and tumor-related anatomical variation may alter cannulation technique. Patients with surgically altered anatomy (Billroth II or Roux-en-Y anastomosis) were also excluded as cannulation technique is then fundamentally different from that in normal anatomy. After giving their informed consent, patients were randomized, using a computer-generated randomization program, to either primary contrast or guide-wire-assisted cannulation (Jagwire; Microvasive Endoscopy, Boston Scientific Corp., Boston, Mass., USA). The proceduralist was informed of which treatment had been assigned immediately after commencement of the procedure.

Data collected included the time to initial and deep cannulation, the number of separate attempts on the papilla before successful cannulation, the number of unwanted pancreatic cannulations or injections during the procedure, the indications, findings, and the endotherapy performed. The institution’s clinical science and ethics committee approved the study protocol before the study started. Informed consent was obtained from all study patients.

Cannulation protocol

The study was performed in a tertiary referral university hospital endoscopy unit which has a dedicated ERCP training fellow. Two senior endoscopists, each with a career experience of over 6000 ERCPs and an annual ERCP caseload of over 400, directly supervised all procedures. Patients without previous sphincterotomy were randomized to common bile duct cannulation with either sphincterotome and contrast injection or sphincterotome and guide-wire cannulation. Successful cannulation was defined as free and deep instrumentation of the biliary tree. A cannulation attempt was defined as sustained contact with the cannulating device and the papilla for at least 5 seconds.

Five minutes were allotted from the first touch of the papilla with the standard double-lumen sphincterotome (Olympus Optical Co., Ltd., Tokyo, Japan) to achieve deep biliary cannulation. If the fellow was unsuccessful, the consultant then attempted using the same technique for 5 minutes. If this was still unsuccessful, crossover to the other technique occurred in the same sequence: first trainee, then consultant. If the consultant failed to cannulate with the randomized technique, crossover to the opposite arm occurred.

If these attempts at cannulation failed, a needle-knife sphincterotomy (NKS) was performed by the consultant endoscopist using a 3-mm-long Olympus needle knife. The cut was commenced from the top of the papillary orifice and extended upwards in 2-mm increments using blended current. The goal was to completely divide the majority of the papillary mound in a controlled stepwise fashion with a single pass, thus unroofing the biliary orifice, which was then selectively cannulated with a guide wire passed through a sphincterotome. All operators used the same technique. The sphincterotomy was then completed in the conventional manner after successful cannulation. Endoscopists could place a pancreatic stent at their discretion during the procedure. Our usual approach has been to place a pancreatic stent to facilitate pancreatic drainage when the duct has been repeatedly instrumented with a guide wire or repeatedly opacified with contrast; this is most commonly performed prior to NKS. The pancreatic stent was also used to protect the pancreatic orifice during NKS and to facilitate biliary localization after NKS. In the interests of the patient, the consultant could proceed directly to NKS without crossover if it seemed that the alternate technique was likely to fail, for example in the case of a very small papilla in which guide-wire cannulation had failed.

Cannulation technique

The preferred technique was to selectively insert the sphincterotome beyond the papilla and into the bile duct atraumatically. In the case of guide-wire-assisted cannulation this was achieved by leading with the guide wire where possible with the experienced nurse assistant gently advancing the guide wire as instructed (Videos 1 a, b ). Once it was clear that a duct had been cannulated, the guide wire was gently advanced, the direction differentiating the pancreatic from the biliary system. During contrast cannulation all injections were made by the endoscopist after the duct was entered. Only small pulses of contrast were injected, so as to achieve verification of selective biliary cannulation with the least amount of contrast possible. With this approach it was possible to minimize the volume of contrast going into the pancreatic duct, and opacification of the pancreatic duct beyond the head of the pancreas was uncommon. The imprecise technique of impacting the sphincterotome into the papilla and injecting contrast was steadfastly avoided.

Follow-up

All patients were assessed clinically at the bedside before discharge from the endoscopy unit. Outpatients remained in the unit for 4 hours after the procedure. Patients with significant abdominal pain were admitted for observation. All patients were asked to have serum collected for determination of amylase and lipase levels the day after ERCP. Telephone interviews were performed by the endoscopy fellow on day 1 and day 30 after ERCP. A diagnosis of PEP was made in the presence of typical abdominal pain associated with a greater than three-fold elevation of serum amylase above the upper limit of normal on day 1 after the procedure.

All ERCP complications, including PEP, were graded according to consensus criteria [21]. If a diagnosis of PEP was made, a gastroenterologist managed all cases, and data were collected prospectively to grade the severity of this complication.

Statistical methods

Prior power calculations assumed a PEP rate of 8 % with the use of primary contrast-assisted cannulation. Assuming a reduction in PEP of the order of 75 %, 206 cases in each arm were required to achieve statistical significance with 80 % power using a Χ² test of proportions and a 5 % significance level. The statistical software package SPSS for Windows Version 14 (SPSS Inc., Chicago, Ill., USA) was used to analyze the data. Mean and standard deviations (SD), or medians and interquartile ranges (IQR) in the case of skewed distributions, were used to summarize data for continuous variables, while percentages were used for categorical variables. The Mann-Whitney test was used to test for differences in continuous outcome variables by type of treatment. The Χ² test, or the Fisher’s exact test when expected cell sizes were less than 5, was used to investigate associations between categorical variables. These univariate tests were taken as exploratory for suggesting candidate variables to be included in a stepwise multiple logistic regression analysis. In the final multiple logistic regression model the effect of each factor was adjusted for those of the other independent predictors in the model. Statistical significance was taken as P < 0.05. No correction for multiple comparisons has been made, all analyses being treated as exploratory and requiring confirmation in further study.

Results

Patients were enrolled prospectively between August 2003 and April 2006, during which period 1654 ERCP procedures were performed. A total of 430 patients with naïve papillae, who met the inclusion criteria, were randomized to undergo either primary guide-wire (n = 215) or contrast cannulation (n = 215). After the procedure was commenced, 17 patients (13 in the guide-wire arm, 4 in the contrast arm), were excluded from the final analysis, primarily because of the presence of unsuspected prior sphincterotomy or surgically altered anatomy.

The final analysis included 413 patients, with 211 in the contrast arm and 202 in the guide-wire arm. The mean age was 59.4 years (18 - 92); 60.8 % of the patients were women. The most common indications were known or suspected biliary calculi or a dilated biliary tree seen on previous imaging ([Table 1]). Suspected sphincter of Oddi dysfunction was the indication in 3.4 %. There was no statistically significant difference between the two treatment arms with respect to the overall distribution of indications.

The overall cannulation success rate was 97.3 %. The fellow commenced in the majority of cases (77.5 %, n = 320). In 323 patients (78.8 %) cannulation was successful with the randomized technique prior to crossover; the corresponding figures were 81.4 % (n = 167) in the guide-wire arm and 73.9 % (156) in the contrast arm (P = 0.03). This difference was consistent for the consultant (74.6 % guide wire vs. 61.0 % contrast, P = 0.02) but not the fellow (50.3 % guide wire vs. 47.9 % contrast, P = 0.67). The median time to successful cannulation without crossover was 120 seconds (range 30 - 322 seconds) for the guide-wire arm and 150 seconds (45-330 seconds) for the contrast arm (P = 0.73). There was no difference between the guide-wire and contrast arms in the median number of cannulation attempts or unwanted pancreatic injections/cannulations. There was no difference in cannulation success according to indication for ERCP. The sequential operator and crossover design of the cannulation protocol limits meaningful analysis when comparing fellow and consultant in relation to pancreatitis and cannulation failure.

In 90 patients cannulation failed to be achieved with the assigned randomized technique within the allotted time. Seventy-two of these patients were crossed over to the alternate technique. Cannulation was successful in 26 of 50 patients crossed over to guide wire and 10 of 22 crossed over to contrast, the remainder requiring NKS. Thus overall in the crossover groups NKS was performed in 36 patients and was successful in 28. Eighteen patients went straight to NKS without crossover (guide wire n = 13, contrast n = 5) and this was successful in 15. There were 11 failures of cannulation overall (7 contrast and 4 guide wire). The NKS rate was 12.4 % and 13.7 % in the guide-wire and contrast arms respectively (P = 0.77).

Biliary sphincterotomy was performed in 93.5 % of patients in the guide-wire arm and 92.6 % of those in the contrast arm (P = 0.77). A pancreatic stent was placed in a total of 20 patients (4.9 %): 7 (3.5 %) in the guide-wire arm (6 of whom underwent NKS), and 13 (6.3 %) in the contrast arm (8 of whom underwent NKS; P = 0.02).

Post-ERCP pancreatitis

PEP occurred in 29 patients (7.0 %). There was no difference in the rate or severity of PEP between patients randomized to the guide-wire arm (7.9 %, n = 16, 13 mild, 3 moderate) compared with the contrast arm (6.2 %, n = 13, 9 mild, 4 moderate; P = 0.48). Seven patients randomized to guide-wire cannulation developed PEP with no pancreatic duct contrast injection. Four of these did not have pancreatic guide-wire cannulation. No severe pancreatitis occurred. At 30-day follow-up all cases of pancreatitis had resolved and no additional complications were identified.

Multivariate analysis identified the independent risk factors for PEP as female sex (OR = 2.70), complete pancreatic duct filling with contrast (OR 3.46), and suspected sphincter of Oddi dysfunction (OR 5.50) ([Table 2]). The risk of pancreatitis increased incrementally with each additional attempt at the papilla, with an odds ratio of 1.39 per attempt (P = 0.04) ([Fig. 1]). There was no statistically significant interaction between the effects of independent predictors and randomized technique leading to pancreatitis.

The median number of unwanted pancreatic injections or cannulations was not independently associated with PEP. In the small group of patients in whom they were used, pancreatic duct stents did not protect against PEP. Whilst failure of cannulation was associated with PEP, it was not an independent factor because it was highly correlated with the total number of attempts.

Discussion

Post-ERCP pancreatitis is the most common complication of ERCP and potentially one of the most serious [22]. A universally applicable, inexpensive, effective, and safe intervention that ameliorates this complication and is broadly applicable to both inpatients and outpatients undergoing ERCP has not yet been identified.

Patient factors which have consistently been associated with increased risk of PEP include younger age, female sex, normal serum bilirubin, previous pancreatitis, previous ERCP-induced pancreatitis, absence of chronic pancreatitis, and sphincter of Oddi dysfunction [11]. Yet ERCP is an important therapy even for patients with an increased risk of developing PEP. Thus careful patient selection and risk-benefit assessment are most important to maximize benefit and minimize harm in the therapeutic ERCP setting.

Various forms of pharmacologic prophylaxis, usually administered before the procedure, have demonstrated modest reduction in PEP in some randomized controlled trials [23] [24] [25] [26] [27] [28] [29] [30] [31]. Unfortunately, in the majority of cases early promise has been tempered by the findings of larger, more carefully designed or multicenter trials and pooled analyses which have failed to show a benefit of the intervention [32] [33] [34].

Inadvertent injection of contrast agent into the pancreatic duct is believed to play a role in the development of PEP, and the degree of pancreatic duct opacification has been shown to be associated with PEP [35]. Placement of a pancreatic stent in those patients at high risk of developing PEP has been proven to be effective for reducing PEP [36] [37] [38] [39]; however, wide variation exists in both patient selection and stent placement technique [40]. Difficult biliary cannulation may also be facilitated by prior placement of a pancreatic stent [41]. Complete pancreatic filling has been shown in other large series to be important in the genesis of pancreatitis [35]. In our practice, pancreatic-stent placement in difficult cases was performed at the discretion of the consultant endoscopist (M.J.B., S.J.W.), primarily to facilitate a NKS. This group of patients was more likely to develop PEP, reflecting an increased number of prior attempts and greater overall difficulty of cannulation in this subgroup [36] [37].

At the time that our study was initiated, no other randomized studies comparing primary guide-wire with contrast-assisted biliary cannulation using sphincterotomes had been published. Since then, one single-operator study has been published with results that demonstrate a reduction in PEP in the guide-wire cannulation arm compared with contrast [42]. In that study, there was no pancreatitis in the guide-wire arm and a pancreatitis rate of 4 % in the contrast arm. The threshold for serum amylase level to define PEP, at five times the upper limit of normal, was greater than that used in the standard literature. Thus this study could potentially underestimate the incidence of PEP in either group. If we had used the “five times upper limit of normal” threshold for the diagnosis of PEP in our study the overall rate would have been 5.3 % (5.9 % guide-wire and 4.7 % contrast, P = 0.59). Although the single-operator study favored guide-wire cannulation, the results are difficult to generalize to a range of endoscopists with varying skills. As the present study involved fellows in training with experienced biliary endoscopists as backup, and thus a broad range of technical aptitude, we believe that it more accurately reflects the current reality of the clinical practice of ERCP.

Our results underscore the importance of the skill and experience of the proceduralist in minimizing PEP, and suggest that successful cannulation with fewer attempts at the papilla is a more important factor than whether guide wire or contrast is routinely used first to achieve biliary cannulation. It appears that both techniques can cause pancreatitis, and the more important observation is the fact that the risk of PEP increases incrementally with each further attempt at the papilla, exceeding 10 % after four or more attempts ([Fig. 1]).

The overall success rate of common bile duct cannulation in the study was 97.3 %. High cannulation rates and low pancreatitis rates necessitate large numbers of patients or a very large difference between treatment arms to show a benefit. Our observed pancreatitis rate of 7 % was close to the rate of 8 % we predicted for power calculations. This study was sufficiently powered to detect a 75 % reduction in PEP and we did not observe this, nor even a trend in favor of guide-wire-assisted cannulation. This is demonstrated by the observation that amongst the 29 patients who developed PEP, 11 did not have contrast opacification of the pancreatic duct, and in 4 of these no pancreatic duct instrumentation occurred. Thus, in the absence of extreme cases where the pancreatic duct is completely opacified, notwithstanding that this may be a surrogate marker of difficult cannulation and repeated attempts at cannulation, the number of attempts at cannulation assumes primacy over pancreatic injection or instrumentation as a critical factor in the genesis of PEP.

Ideally, beyond patient selection, operator skill and experience, and pancreatic duct stenting in high-risk cases, we believe that the best opportunity to minimize the occurrence of PEP is atraumatic, single-pass, selective deep biliary cannulation.

Conclusion

In conclusion, the guide-wire technique improves the primary success rate for biliary cannulation during ERCP but does not reduce the incidence of PEP compared to the conventional contrast technique. The incidence of PEP increases significantly in an incremental fashion with each attempt at the papilla.

A technique which can offer consistent selective, single-pass, atraumatic, deep biliary cannulation will have the greatest potential to truly ameliorate the occurrence of PEP. The guide-wire technique holds promise as it offers superior primary cannulation rates; however, as currently described it has not been shown to reduce the incidence of PEP. It merits further refinement and study.

Competing interests: None

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M. J. Bourke, MD 

Gastroenterology and Hepatology
Westmead Hospital

106A/151 Hawkesbury Rd
Westmead, Sydney
Australia 2145

Email: michael@citywestgastro.com.au

References

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M. J. Bourke, MD 

Gastroenterology and Hepatology
Westmead Hospital

106A/151 Hawkesbury Rd
Westmead, Sydney
Australia 2145

Email: michael@citywestgastro.com.au