by: Dr YAMA SENGERWAL
A Critique of Five Studies: Endoscopic Ultrasound (EUS) versus Endoscopic Retrograde Cholangiography (ERCP) in Diagnosis and Management of Choledocholithiasis
Choledocholithiasis is the presence of calculi or stones in common bile duct (The Merck Manual). The common bile duct is the main tube that carries bile from the gallbladder and liver into the duodenum. The common bile duct is formed by the junction of the cystic duct that comes from the gallbladder, and the common hepatic duct that comes from the liver. The transportation of bile from the liver to gallbladder for storage, and from gallbladder to duodenum is an important requirement of the gastrointestinal apparatus which can only occur in presence of a patent and functioning common bile duct. The bile helps with the digestion of the fatty food (Medline Plus, 2010).
The obstruction of common bile duct not only hinders the delivery of bile to the duodenum, it also entails serious complications that may require urgent radiological and/or surgical intervention. These complications can include biliary colic, cholecystitis, pancreatitis, and cholangitis. There are various causes for the obstruction of the common bile duct. Some of these causes include adhesion following infection, cancer, and gallstone.
Calculi can form in the gallbladder or in the ducts themselves. They cause bilary colic, biliary obstruction, gallstone pancreatitis, or cholangitis. Cholangitis, in turn, can lead to strictures, stasis, and, potentially, hepatic pathology.
Studies have shown that gallstones, and the complications associated with them, is a significant problem especially in developed world. The prevalence of gallstones among adults in North America and European population ranges from 10 to 20 per cent, highlighting the significance of having diagnostically and therapeutically effective and economically affordable techniques to help with the management of choledocholithiasis and its complications.
It is paramount to achieve an early diagnosis of the problem to prevent the potentially fatal complications. Traditionally, the diagnosis usually requires visualization by magnetic resonance cholangiopancreatography, or ERCP. The ERCP is both an effective diagnostic, and a potentially therapeutic tool in management of Choledocholithiasis. ERCP cannot be replaced completely with other available methods. However, recently there has been significant debate in scientific papers with regards to the efficacy, safety and cost effectiveness of the ERCP in comparison to the newer imaging technologies.
This article will review five papers that compare different aspects of the ERCP and Endoscopic Ultrasound (EUS) in diagnosis and management of Choledocholithiasis. An argument made by Savides (2008) states that EUS has become widely available in community hospitals and provides similar or better diagnostic information without the risk s associated with ERCP.
The ERCP is still known, by many, as the “gold standard” procedure for preoperative visualisation of the bile duct, owing to its ability to be both a diagnostic and therapeutic modality in management of choledocholithiasis. However, the non-selective use of ERCP in the management of all patients with suspected choledocholithiasis detects CBD stones in only 50% of patients, which means that over half of the patients with suspected choledocholithiasis undergo unnecessary invasive procedure with its attributable morbidity and mortality. The hypothesis is that the use of EUS in diagnosis of choledocholithiasis has a much greater accuracy and is safer than ERCP.
A literature review is an overview of the literature in the general topic area of the research. It uses systematic and explicit methods to select and critically appraise relevant research literature, (Holloway 1997). For the purpose of this study five articles that address the research question were selected and critically reviewed. They were selected from a thematic matrix of ten articles. The method facilitated comparisons to be made to evaluate suitability of these articles. By formulating an inclusion and exclusion criteria, the five articles most relevant to the research question were then chosen.
1. Lee YT, Chan FK, Leung WK, Chan HL, Wu JC, Yung MY, Ng EK, Lau JY, Sung JJ. (2008) Comparison of EUS and ERCP in the investigation with suspected biliary obstruction caused by choledocholithiasis: a randomized study. Gastrointest Endosc. 67(4):660-8.
This randomised study aims to investigates the benefits and safety of a EUS-guided versus ERCP-guided approach in the management of suspected biliary obstructed disease caused by choledocholitiasis. It starts with a rather lengthy and less concise title, and as David Cowan states, the title of a paper “should comprise a concise, succinct and clear description (of the research)” (David Cowan 2009).
The authors of this study are MD doctors and PhD holders from the Institute of Digestive Disease, Chinese University of Hong Kong, and Prince of Wales Hospital, Shatin, Hong Kong, who between them have contributed to the publication of 3779 studies.
The study contains a concise abstract that identifies the research theme, outlines the method, and states the major findings. The authors have clearly explained the problem and have identified the rationale behind the study. However, they fail to mention some of the limitations in the study which could have affected the validity of their findings. For example the authors have not appreciated the fact that their subject population is a relatively small number of 65 patients. The readers shold ideally be aware of the size of the sample earlier in the article before committing their time to reading the entire paper.
The authors have assigned their subjects randomly to either sEUS or ERCP group by use of concealed envelopes. This approach is congruent with a randomised study, which the authors claim to have carried out. The ERCP procedures were performed by 6 different endoscopests with an experience range of 3 to 15 years. Some might argue that this subjects the findings to a significant observation and interpretation bias. Those cases reported by investigators who have 15 years of experience could be in advantage over those who are reported by less experienced investigators.
Although the authors state that the study was approved by the ethics committee of the university, some might still question the safety consideration for one particular group of participants. The authors believe that performing EUS before a therapeutic ERCP is safe for patients. Assigning half of the participants to the ERCP-only group, despite knowing that ERCP is less safe for participants, might raise some ethical questions regarding patient safety.
2. Janssen J, Halboos A, Greiner L. (2008) EUS accurately predicts the need for therapeutic ERCP in patients with a low probability of biliary obstruction. Gastrointest Endosc. 68(3):470-6.
This prospective study is carried out by a number of academics from Department of Medicine, University of Witten/Herdecke, Wuppertal, Germany. The study has been published in Gastrointestinal Endoscopy, a peer-reviewed journal with an impact factor of 6.713. (Website of Gastrointestinal Endoscopy, Official Journal of the American Society for Gastrointestinal Endoscopy 2010). The Authors have contributed to 221 papers between them.
The title of the article is concise, but falls short of sufficient information about the contents of the paper. For example, it gives no reference to the method used to accomplish the findings, which is an essential requirement for a good comprehensive paper. This deficiency, however, has been addressed by the abstract of the article, which covers the entire length of the study, including the study design, the method, the findings and conclusion.
The method clearly outlines the different steps taken in the study. It states the inclusion criteria, but gives no clear account of the exclusion criteria for the study. It mentions that all the participants were divided into four main groups depending on their presenting complaints. The authors rightly acknowledge the fact that the study was “unblended”, which is one of the few weaknesses in the study. The other noticeable shortcoming is the fact that the study has relied on a very small subject population of 50.
The study is ethically correct in the sense that it obtains a written informed consent from every individual participant.
The discussion part of the paper evaluates the practical details of the procedures, which are essential, but it does not do enough to give a balanced evaluation of the statistical and operational aspects of the study. For example, it does not explain how they base their conclusions on the findings of a study that only includes 50 patients.
This study can be improved by expanding the subject population, and performing a multi-centre work, a recommendation that authors fail to give. Overall the study does confirm the findings of a growing number of other studies that acknowledge EUS as an effective, accurate, and safe procedure that can significantly reduce the number unnecessary ERCPs, which is more invasive, and can lead to significant complications for clients.
3. Karakan, T., Cindoruk, M., Alagozlu, H., Ergun, M., Dumlu, S., Unal, S. (2009) EUS versus endoscopic retrograde cholangiography for patients with intermediate probability of bile duct stones: a prospective randomized trial. Gastrointest Endosc., 69, 244-52.
The title of the study is concise and informs about the type of the study (i.e. a prospective randomized trial), the aims (EUS versus endoscopic retrograde cholangiography) and target patient population (patients with intermediate probability of bile duct stones). Thus the title clearly indicates the content and the research process used. An abstract is included in the study and is described heading wise. The abstract gives clear information in a concise manner about various aspects of the study, and identifies the research problem, i.e., “factors affecting diagnostic accuracy and comparison of patients in the follow-up period for negative outcomes are not thoroughly investigated in a randomized trial.” The methodology, sample subjects and major findings in the study are mentioned in the abstract.
The literature review in the study, however, is not very comprehensive and is very short, but it is up-to-date. No underlying theoretical frameworks have been identified in the study. However, the literature review does identify the need for the research proposal. There is no hypothesis in the study. The methodology is clear. The study is a prospective unicentric randomized study conducted over one year after appropriate approval from the relevant Ethics Committee. The aims and objectives in the study are clear and well defined. Even secondary objectives are indicated. All the terms in the research are clearly defined. A standardized criteria defined by Barkun et al was used to determine common bile duct stones. The methodology is clear, reproducible and appropriate to the research problem. The inclusion criteria and exclusion criteria for this study are clearly defined and described in an elaborate manner.
The strengths and weaknesses of the approach are not stated. The subjects in the study are clearly identified and the sample selection is congruent with the method used for the study. The sample size is 60 per group and is clearly stated, and the approach to sample selection is clearly identified. The procedures for data collection are adequately described. However, the validity and reliability aspects are not clearly stated (Rothwell, 2005). This study has been approved by an ethical committee and has no ethical implications (Freedman, 1987). Informed consent of the participants of the study was sought, but there is no assurance of confidentiality and anonymity is not guaranteed (Gifford, 1995).
The results of the study are internally consistent and presented clearly in tabular form, making it easy to comprehend. The discussion is balanced and draws upon previous research, which has been referred to appropriately. The clinical implications of the study are discussed and the conclusions are well supported by the results. In the conclusion, improvements on the limitations of the study and scope for further research are discussed.
4. Sotoudehmanesh R, Kolahdoozan S, Asgari AA, Dooghaei-Moghaddam M, Ainechi S. (2007) Role of endoscopic ultrasonography in prevention of unnecessary endoscopic retrograde cholangiopancreatography: a prospective study of 150 patients. J Ultrasound Med. 26(4):455-60.
The title is concise and indicates the type of research undertaken. However, it is vague because the term ‘role of’ does not indicate a specific outcome measure. Broadly speaking, the content of research can be gauged through the title. Thus, it can be said that the title is semi-informative. All five authors in the study hold Master’s degrees in medicine and are gastroenterologists. The abstract of the study has been provided and it describes the study in a concise manner with the use of specific headings. However, it does not identify the research problem. The paper starts with an up-to-date account of the existing knowledge of the topic, but is not exhaustive. The limitations of the study are described in the discussion, but are not clearly stated at the beginning.
The operational definitions of the procedures studied and the participants are well defined. All the terms described in the research question are well defined. The methodology used describes a prospective study and is well defined. While the methodology clearly states the research approach used, i.e. a prospective study, there is no mention of the positive and negative outcomes of the use of this type of approach (Benson and Hartz, 2000). The subjects are patients referred to the department with suspected choledocholithiasis, biliary colic and acute biliary pancreatitis, on the basis of a rise in liver enzymes, with or without evidence of gallstone seen on transabdominal ultrasound. The selection of the sample is plainly stated with clearly described inclusion criteria, i.e. patients with low or intermediate risk factors for presence of CBD stones. The low and intermediate risk patients are clearly defined. The authors, however, fail to state the reason behind their decision not to include patients with high risk for the presence of CBD stones.
The sample size is clearly stated. Collection of data is adequately described and reproducible. Informed consent was taken but guarantee of anonymity and assurance of confidentiality is not made. The results of the study are clearly made, but it is unclear whether they are consistent internally. The results are presented in the form of charts, which enhance the clarity of the results. Data analysis was done manually because it is a prospective study (StatsDirect, 2009). The weaknesses of the study are acknowledged and various clinical implications are discussed. The conclusion is very short and is based on the results of the study. Scope for future research and clinical implications are briefed under conclusion, but there is no clear recommendation for performing a more reliable and better study in the future.
5. Artifon E. L., Kumar A., Eloubeidi M. A., Chu A., Halwan B., Sakai P., Bhutani M. S. (2009) Prospective randomized trial of EUS versus ERCP-guided common bile duct stone removal: an interim report (with video). Gastrointestinal endoscopy Volume 69, No.2.
This prospective randomized study by Everson et al (2009) was intended to study and assess the effectiveness and safety of EUS-directed common bile duct (CBD) stone removal in comparison to ERCP-directed intervention. All the authors possess masters degree in medicine and two of the authors possess PhD degrees. They are gastroenterologists with a keen interest in study and research pertaining to stones in bile ducts. Thus the authors have professional experience and qualifications in this regard (Brunel University 2009).
The abstract of the article wraps up the introduction and method of the study, and clearly illustrates the objectives of the study and its overall findings. This can easily allow the reader to understand the nature of study. The discussion is well balanced and draws upon previous research pertaining to the research question.
In the introduction the two investigative procedures, EUS and ERCP, and their role in bile duct stone removal are defined appropriately and in detail. It also explains the problems that occur during the endoscopic procedure. This informs the reader of the need for further research on the topic.
The method of the study is appropriate to the research objectives. Fifty two patients were prospectively randomized for this study, which is a relatively small number of participants for this study. Those participants who were not willing to participate or unable to provide written consent were excluded from the study. This is an ethically desirable research attitude, as authors are required to describe in their manuscripts how consent was obtained from participants when research involves human participants. The rationale for the study is clearly mentioned, however the limitations of the study are not stated.
The results are only presented in the text format. A graphical or tabulated version of the results is not available, something that has reduced from the clarity of the results, and intelligibility of the paper. The amount of data and figures presented as results seem to be less than sufficient for a research of this scope. It seems from the report that the authors have provided video clips of the procedures to support their findings. This could enhance the validity and objectivity of the findings, as other researchers can refer to the video clips and re-evaluate the potential aspects of the study.
The argument forwarded by these five studies, and many others in the scientific literature is that while ERCP is an essential and unavoidable modality in the treatment of common bile duct stones, it is possible to reduce the unnecessary use of ERCP by a significant proportion. Where the ERCP is the only well-practised procedure to remove a common bile duct stone, it is not the only diagnostic procedure to diagnose choledocholethiasis. The above studies suggest that EUS is a sensitive, safe and cost effective diagnostic procedure that can reduce the eventual unnecessary and non-selective use of ERCP.
The outcomes of the above studies loosely agree on the prospect of EUS being a favourable procedure to preclude the need for ERCP, especially in cases with low and intermediate risk for common bile duct stones. Four out of five studies suggest the EUS as a safer and more accurate modality, while one study finds it equally effective, and calls for further research to determine predictors of success of EUS guided stone-removal.
The above papers between them study 405 individuals with suspected common bile duct stones, a number large enough to enhance the validity of their common conclusion. They employ prospective approaches with mostly randomised designs. The studies cover all the important aspects of EUS investigation, and together make a good case for this relatively young modality to be considered as a safer, more accurate, and cost effective alternative to ERCP in investigating patients with low and intermediate risk for common bile duct stones.
One of the above papers (Jansen et al) studies the accuracy of the EUS as a predictor for performing therapeutic ERCP in 50 individuals who presented with either clinical, biochemical, or transcutaneous ultrasonic suspicion of biliary obstruction. The study finds that as a result of performing EUS investigation prior to ERCP in this group of patients, only 7 out of 50 patients were identified to genuinely need ERCP. This means that if the EUS was not performed, 86% of the patients would have undergone unnecessary ERCP.
Similar accuracy with similarly significant reduction in ERCP number has been reported elsewhere by other studies. Ainsworth et al. and Polkowski et al. have found up to 95% reduction in the use of diagnostic ERCP as result of use of EUS. Therefore the finding of this study regarding the accuracy of EUS has been reproduced before in the literature. One criticism that this study (Jansen et al) may receive is the use of simplistic statistics. The study fails to use advanced scientific analysis on the results, and only uses simple arithmetic calculations to support its verdict on the accuracy of the EUS.
The other two studies in this critique (Rotoudehmanesh et al and Lee et al), in addition to the accuracy of EUS, also focus on the safety of EUS as an alternative diagnostic procedure to ERCP. Both studies, using similar outcome measures, conclude that diagnostic ERCP can be avoided in a significant proportion without causing any further complications. None or little complications were associated with EUS procedures in the group of patients studied in these papers. The percentage of avoided diagnostic ERCP procedures was still significantly high.
Although the evidence is in support of EUS as a better and safer alternative is mounting, one should bear in mind that EUS can only be an alternative to diagnostic ERCP in low and intermediate risk patients. The ERCP still needs to be performed if the EUS proves the existence of a common bile duct calculus. While the success of EUS does not discredit the therapeutic use and importance of ERCP, it emerges as a diagnostic tool to replace the diagnostic use of ERCP. By using the EUS as an alternative diagnostic tool, clinicians can avoid serious complications associated with ERCP namely pancreatitis, cholangitis, haemorrhage, and duodenal perforation.
The papers reviewed here investigate the important aspects of the EUS modality including safety, effectiveness, accuracy, cost-effectiveness and the rate of subsequent post procedure complications. However they fail to consider some other parameters that can be pivotal for a new diagnostic tool to be accepted by, and used in clinical practice. Research needs to be done, for example, to find out whether the possibility of undergoing two procedures (EUS and ERCP) is acceptable for the patients, as performing ERCP will be essential if EUS does show a common bile duct stone. Some patients (we do not know what proportion) might prefer to risk undergoing ERCP in order to avoid undergoing both procedures, i.e. both EUS and ERCP. Undergoing EUS before a possible ERCP may prolong patients stay in hospital, and possibly the suffering cause by a possible common bile duct obstruction.
Since EUS is a relatively new modality, there is no data available in scientific literature regarding the long term safety and usefulness of EUS as a diagnostic tool. Despite all the evidence confirming the accuracy of the modality, a hundred percent sensitivity and validity is not guaranteed. This should suggest that EUS is only a relatively better modality for the diagnosis of cholidocholithiasis at the present moment, and other means of investigating the bile ducts should be developed.
There are a number of other well known means of investigating bile duct stones. These include Magnetic Resonance Cholangiography, and Computed Tomographic (CT) Cholangiography. These modalities have been used in clinical practice, and studied in medical research. The use of CT Cholangiography is limited by the intravenous contrast agent use, and involvement of high doses of radiation. Magnetic Resonance Cholangiography, on the other hand, has a much stronger case. It is a safe and non-invasive procedure with a reliable multi-disciplinary use. Research has showed no statistically significant difference between the diagnostic performances of EUS and MRCP (Verma 2000). MRCP, however, is contraindicated in certain group of patients namely patients with metal parts in-situ, and claustrophobic individuals. Other “potential problems with magnetic resonance cholangiography are image artefacts and difficulty in patient compliance; it is time consuming; and its accuracy for detecting biliary stones in an undilated CBD is not optimal.” The above arguments add significant weight in support of the common hypothesis of reviewed papers.
The fifth study reviewed in this work has taken a further step in safe management of cholidocholithasis. The paper conducted a prospective, randomised clinical trial to evaluate the effectiveness and safety of EUS-guided CBD stone removal. The study finds that a EUS-guided stone removal is at least as safe as ERCP. The preliminary results reported by this paper indicate no additional complications associated with EUS-guided CBD stone removal. The paper, however, lacks a description of what the authors exactly mean by EUS-guided stone removal, and how it differs from ERCP.
Finally, the findings of the above papers can have significant implications for policy and practice, both on a national and local level. Many health authorities across the country have already invested in EUS technology and expertise. These centers have already benefited from the new modality in terms of avoiding risky and potentially expensive use of diagnostic ERCP. Incorporating EUS in clinical practice also means a significant shift of work load and resources to imaging departments. This requires an appropriate expansion in managerial and departmental facilities.
The findings of these papers may have significant ethical implications for clinical practice. One might argue that the use of ERCP must only be limited for therapeutic use, since a much safer and more accurate modality, i.e. endoscopic ultrasonography, exists. The unnecessary use of ERCP might be considered as an ethically inappropriate practice.
There is further room for research in this area. As mentioned earlier in the text, there is no data available on the long term safety of EUS. Furthermore, research is needed on a currently less studied version of the EUS, EUS-guided CBD stone removal. Also, the findings of these studies need to be approved by national health authorities like the NICE in order to be presented and used as clinical guidelines in management of cholidocholithiasis.
- Ainsworth, A.P (2003) “Is there a difference in diagnostic accuracy of and clinical impact between EUS and MRCP?” Endoscopy 35, pp.1029-1032.
- Anand,V et al (1999) “bile duct stones and laparoscopic cholecystectomy” Gastrointestinal Endoscopy, 49(3),334-343.
- Benson, K., Hartz, A.J. (2000). A comparison of observational studies and randomized, controlled trials. N Engl J Med., 342 (25), 1878–86.
- Burns, N. Grove, S. (2004) The Practice of Nursing Research: Condct, Critiquing, and Utilization. 4th edn. Saunders.
- Clegg B. (2001) the professional’s guide to mining the interney. 2nd edn. London Kogan page.
- Concato, J., Shah, N., Horwitz, R.I. (2000). Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med., 342 ,(25), 1887–92.
- 7. Cormack,D. (2000) The research process in nursing. Blackwel
- Frances,T et al (2008) “EUS: a meta-analysis of performance in suspected choledochollithiasis” Gastrointestinal Endoscopy, 67 (2), pp.235-244.
- Frank.C (2006). Endoscopic Ultrasound: an introductory Manual and Atlas.1st edn. Thieme Medical Publisher.
- Freedman, B. (1987). Equipoise and the ethics of clinical research. N Engl J Med., 317 (3), 141–5
- Gifford, F. (1995). Community-equipoise and the ethics of randomized clinical trials. Bioethics, 9 (2), 127–48.
- 12. Holloway.I (1997) Basic Concepts of Qualitative research. 2nd edn. John Wieley and sons Lit.
- Loperfido,S and Costamagna,G (2010) Rare Complications of ERCP. Available at: http://www.uptodate.com/patients/content/topic.do?topicKey=~90031/tyrailib3 (Accesses: 13 September 2010).
- Parahoo, K. (2005) Nursing Research principles, process and issues. 2nd Edn. Basingstoke, Hampshire. Palgrave Macmillan.
- Petrove,S. Savides,T.J (2009) “systematic review of EUS versus ERCP for suspected choledocholithiasis” British Journal of Surgery, 96, pp.967-974.
- Polkowski,M et al (2007) “ EUS versus ERCP for patients with intermediate probability of bile duct stone” Endoscopy 39, pp.296-303.
- Rothwell, P.M. (2005). External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet, 365 (9453), 82–93.
- 18. StatasDirect. (2009). Prospective vs. retrospective studies. Retrieved on August 15th 2010 from http://www.statsdirect.com/help/basics/prospective.htm
- Thoma,J and Savides, MD (2008) “EUS-guided ERCP for patients with intermediate probability for choledocholithiasis” American Society of Gastrointestinal Endoscopy. 67, (4) pp. 669-672.
- Trap R et al (1999) “Severe and fatal complications after diagnostic and therapeutic ERCP” Endoscopy. 31 (2): pp125-130.
- Verma. D (2006) “EUS vs ERCP for detection of choledocholithiasis” Gastrointestinal Endoscopy. 64 (2): pp248-256.
- Wood.G.B and Haber.J( 2006) Nursing: method and critical appraisal for evidence. 6th edn. Elsevier health Science.