The selection from international journals

Summary

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is the most prevalent and harmful side effect of diagnostic and therapeutic ERCP. Identifying high risk patients and subsequent selection of alternative diagnostic methods needs a multifactorial study of PEP (post-ERCP pancreatitis) risk variables. To determine the most hazardous PEP-related variables, a systematic study was conducted. In order to find relevant studies published between 1/1/2017 and 1/10/2022, two independent researchers conducted searches (MT, SH R). A literature search of English language publications was conducted using MEDLINE through PubMed, EMBASETM through Ovid, the Cochrane Library, and Trip. In addition to Magiran and SID, we searched KoreaMed and LILACS for literature published in other languages. Endoscopic retrograde cholangiopancreatography OR Pancreatitis OR Risk factors OR ERCP OR Systematic review were used in the search strategy. A total of 174 studies were selected. After analyzing their compliance with the required criteria, a final review of five studies was conducted. This article presents the current findings on the most critical risk factors for post-ERCP pancreatitis. The most frequent ERCP operation side effect is PEP, which concerns individuals with high-risk factors. There is significant debate over PEP‘s pathophysiology. Due to its complex pathophysiology, PEP prevention should include a variety of criteria, including patient-related risk factors, pharmacological prophylaxis, and procedural methods. The patient‘s age, gender, and previous history of the disease are the most critical risk factors for pancreatitis after ERCP.

Keywords:

pancreatitis – endoscopic retrograde cholangiopancreatography – risk factors – ERCP – PEP – systematic review

Background

Since Thomas Starzl conducted the first liver transplant in 1963, transplant procedures, immunosuppression, and patient selection have all advanced steadily. This has unquestionably transformed how end-stage liver disease is managed (ESLD). The total number of liver transplants performed during the past 20 years has increased nationally and internationally. Nearly 30,000 transplants were performed globally in 2018 [1]. Orthotopic liver transplantation is the only effective treatment for hepatocel lular carcinomas and end-stage liver disease. Despite advancements in surgical procedures, graft preservation methods, and immunosuppressive drugs for liver transplantation, biliary issues continue to be a significant cause of morbidity and mortality in patients receiving liver transplants and are a vital determinant in graft survival [2,3]. With a frequency of 10–25%, biliary problems are the most frequent post-transplant complications. Recipients of liver transplants from both deceased and living donors might experience these problems. There are various methods for diagnosis and treatment of these biliary complications (endoscopic, radiological, or surgical), of which ERCP is the most used [4,5].

The endoscopic treatment known as ERCP has gained popularity since its debut in 1968. ERCP‘s diagnostic and therapeutic utility has been effectively demonstrated for various diseases, including managing biliary perioperative issues, diagnosing and treating biliary and pancreatic neoplasms, and therapy of choledocholithiasis. In post-transplant therapy, endoscopic treatment of biliary problems with ERCP has established itself as a staple [6–8]. ERCP is selected as the initial course of treatment since it aids in validating the diagnosis and makes therapy possible. Cholangitis, pancreatitis, hemorrhage, perforation, and, in rare cases, death are only a few risks associated with ERCP. Between 4 and 12% of ERCPs have recorded complications in the general population [7,9].

Early detection and prompt treatment of known biliary problems after transplant have been demonstrated to minimize morbidity and mortality and enhance graft survival. ERCP treatment is relatively low-risk and highly effective after a liver transplant [10].

The most frequent post-procedural consequence following ERCP is pancreatitis. Its reported incidence ranges from 2.1 to 24.4%, with the wide variation being attributed to the different patient groups, varying degrees of endoscopic skill, procedural variations, varying definitions of post-ERCP pancreatitis (PEP), and the severity of the condition [11].

Even though up to 75% of patients may experience a temporary rise in pancreatic blood enzymes, this does not always indicate pancreatitis. A commonly accepted definition for post-ERCP pancreatitis (PEP) includes the following:

1. new or worsening abdominal pain;
2. new or prolonged hospitalization for at least two days; and
3. serum amylase measured more than 24 hours after the procedure that is three times or more the upper limit of normal.

In a meta-analysis of 21 prospective trials using these criteria or ones close to them, the incidence of PEP was around 3.5 percent. However, the range depends on the patient population (1.6 to 15.7%). Pediatric patients experience PEP rates similar to those observed in adults. Even if a multifactorial idea is embraced, the pathophysiology of PEP is not established. It is brought on by several injuries, including those caused by papillary instrumentation and/or hydrodynamic damage from the pancreatic duct being overfilled with contrast material. These insults include chemical, thermal, mechanical, hydrostatic, enzymatic, allergenic, and microbio logical damage. These factors have a cascade effect that results in autodigestion, early intracellular activation of pancreatic proteolytic enzymes, and the generation of inflammatory cytokines with local and systemic effects [11,12]. Cannulation trauma to the papilla is one of the pathogenic causes of PEP that most frequently results in the sphincter of Oddi spasms and/or papilla edema. It prevents the pancreatic juice from flowing normally, which causes acute pancreatic inflammation. Another crucial aspect is the contrast medium, whose osmolarity and ionic composition are thought to be the main contributing variables [13,14].

Strategies for prevention that target risk variables may be crucial to lowering the incidence of post-ERCP pancreatitis. The causes of PEP, however, are still up for dispute.

Methods

A systematic search of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15]. The following search technique was used between 1/1/2017 and the end of 1/10/2022 to find the eligible studies. Two separate researchers (MT, SH R) searched for the pertinent papers published between 1/1/2017 and the end of 1/10/2022. The Cochrane Library, Ovid, and Trip databases searched for English-language publications in MEDLINE, EMBASETM, and MEDLINE via PubMed. Our search for material written in different languages included national databases (Magiran, SID), KoreaMed, and LILACS. For literature saturation (MT), the list of included references or relevant reviews was examined. The Health Sciences Librarian website was used to develop unique search techniques focused on systematic review searches using MESH terms and open phrases in compliance with the PRESS criteria. Results from searches in other databases were contrasted with those from the MEDLINE approach after it had been finalized (MT, SH R). Similarly, PROSPERO was looked up to locate recent or active systematic reviews. The terms Endoscopic retrograde cholangiopancreatography OR Pancreatitis OR Risk factors OR ERCP OR PEP OR Systematic review were utilized in the search approach. The database of earlier study materials and systematic reviews was also explored to find the published research (MT, SH R). A search for unpublished data and abstracts (MT) was also conducted on all papers that met the inclusion criteria.

Eligibility criteria

The addition of cross-sectional, case-control, cohort, case report and review publications were the articles that met the criteria for the systematic review. Non-random sample size, lack of relevance, and inadequate data were among the exclusion criteria. Two researchers carried out each of the stages mentioned above separately to prevent bias in the study. Finally, the consistency of the third researcher‘s findings was checked.

Study selection and data extraction

All pertinent publications were initially gathered, and a list of abstracts was created to help special investigations. The complete text of the publications was given to the researchers after the specifics, such as the name of the magazine and the author, had been concealed. Two researchers independently examined each publication; the reason was stated if the article was rejected. In the event of a dispute between the two researchers, a third researcher evaluated the paper. A general overview of the study (first author, country, and year of publication) and study details (study design, study period, incidence of PEP and number of participants) were extracted (Tab. 1).

Results

Study selection

In the first phase of our comprehensive search, 174 studies were obtained. By reviewing the titles and abstracts, 65 studies were excluded. After a complete review of the text and considering the inclusion/exclusion criteria, 18 studies were excluded, and finally, 4 studies were chosen as appropriate for systematic review (Fig. 1).

For the treatment of pancreatic and biliary tract illnesses, ERCP is the recommended method. Even if ERCP technology and equipment have advanced recently, the prevalence of PEP has not significantly decreased. The most severe and frequent ERCP consequence was PEP. A critical clinical challenge is identifying PEP risk variables, crucial to identifying high-risk patients and selecting alternative therapies. Several prospective studies found discrepancies between the risk variables for pancreatitis following ERCP. Initially, several multicenter studies helped us understand the risk factors for PEP [16–21]. According to research by Guo Zhen Li et al., fistulotomy, deep pancreatic wire pass surgery after liver transplantation, and endoscopic metal biliary endoprosthesis are significant risk factors for pancreatitis following ERCP [22]. The results of Y. Lin et al. showed that the occurrence of PEP is associated with age less than 60 years, the development of the pancreatic duct, the difficulty of intubation, and the long operation time. Among them, pancreatic ductal development and age under 60 are independent of PEP risk factors. Postoperative placement of nasobiliary drainage catheters, prevention of pancreatic ductal dilatation, improvement of intubation success rate, reduction of ERCP procedure time, and other procedures can effectively reduce the incidence of PEP [23]. According to prior research by other authors, the findings of a study by E. Syrén et al. revealed that PEP risk was much higher in women, patients under 65, and those who had previously experienced acute pancreatitis [24–29]. In line with earlier research on hypertriglyceridemia, hyperlipidemia was also discovered to raise the risk of PEP [30,31]. As in other studies, liver cirrhosis was not identified as a risk factor for PEP [32,33]. In the study of E. Syrén et al, contrary to previous studies [34,35], diabetics have a higher chance of having their PEP lowered in cases of acute pancreatitis. After accounting for age and sex, multivariate analysis supported this. Previous research has revealed that the kind of diabetic medication that people take affects their chance of developing acute pancreatitis. The most significant risk factors for pancreatitis following ERCP are often the patient‘s age, gender, and medical history.

Risk factors for pancreatitis after ERCP

Apart from the main risk factors mentioned above, in various studies, other reasons for the occurrence of pancreatitis after ERCP were stated, which include: History of pancreatitis in previous ERCP, Sphincter dilatation with a balloon, Problems in the sewerage, The possibility of dysfunction of Oddi‘s sphincter, Sphincterotomy, More than one injection of contrast material, Absence of gallstones, female sex, Normal bilirubin level, Absence of chronic pancreatitis, age below 60 years, Pancreatic duct opacification, Use of pre-cut sphincterotomy, CBD with a diameter smaller than ten millimeters and Direct heat damage to the Papilla.

Discussion

Generally, ERCP applications can be divided into three groups:

a) biliary tree disorders;

b) pancreas disorder;

c) ampulla of Vater disorders.

Also, this method is widely used for taking samples from lesions of the pancreatobiliary area and for palliative actions [36].

Even though this method has no place in diagnosing acute pancreatitis, it is widely used in recurrent and chronic pancreatitis and is very important in reducing future injuries and mortality caused by it. ERCP is an essential specialized endoscopic technique for examining the pancreatobiliary system, which is increasingly used in liver and digestive centers. With the improvement and progress in the imaging field, including endosonography and MRCP, the therapeutic role of ERCP has become more prominent. Currently, more than 500,000 ERCP treatments are performed annually in the United States of America. Considering the relative complexity of the work and the possibility of ERCP complications, it is necessary for the people who perform it to adhere to the indication, use the proper equipment and way of anesthesia and monitor the patient during and after the operation. They need excellent teamwork; complications accompany ERCP like any other therapeutic and diagnostic operation. The complications are related to the disease‘s severity and the operation‘s complexity.

PEP is still a significant ERCP complication that can adversely affect morbidity, mortality, and patient quality of life. Its complex etiology is not yet fully understood. Clinical investigations have examined several PEP preventive strategies. Studies looking into the prevention of PEP may be divided into three categories:

1. patient-related risk factor evaluation;

2. pharmacoprevention, and

3.
procedural prevention approaches [37].

One of the most crucial elements in PEP prevention is identifying people with high-risk characteristics. High--risk patients should undergo rigorous evaluation, and ERCP may not be the best option for them if other therapeutic and diagnostic methods are avail able. For these individuals, it may be better to forgo ERCP in favor of EUS, MRCP, and other non-invasive procedures such as radionucleotide-labeled scans, percutaneous drain fluid analysis, and other procedures that provide highly accurate findings in detecting pancreaticobiliary disorders [38].

To lessen the probability of PEP development, pharmacological medicines with very accurate outcomes shown in the literature, such as NSAIDs, might be helpful. NSAIDs (indomethacin and diclofenac), widely used and the most promising choice for preventing PEP, have been studied using data collected from patients with ERCP, even though various pharmacologic agents have been examined. All high-risk patients should get NSAIDs intravenously, and individuals with moderate risks should also be considered. Alternatives to explore for the prevention of PEP include several pharmacological medications that have been consistently found to influence the prevention of PEP in diverse investigations [39]. However, in a double-blind, randomized clinical trial study conducted by Esmailzadeh et al between February 2011 and October 2012 on 164 patients with gallstones who needed ERCP, they concluded that the administration of diclofenac had an effect on reducing the incidence of pancreatitis and There was no bleeding complication after ERCP. Of course, according to previous studies that have proven the influential role of non-steroidal anti-inflammatory drugs in reducing the incidence of pancreatitis after ERCP, recommending the Use of this drug category for prevention is a wise thing in the present study, perhaps because of the sample size and interfering factors such as The presence and intervention of digestive fluid may have caused the difference in the result. Of course, some previous studies had similar results and did not confirm the effect of non-steroidal anti-inflammatory drugs in preventing pancreatitis after ERCP [40].

In the study conducted by Sotoudeh Menesh et al., drug prevention of acute pancreatitis after ERCP with 100 mg “indomethacin rectal” suppository, 5 mg sublingual tablet “isosorbide dinitrate” and „Ringer lactate“ serum were investigated. The results of the investigations in this study have indicated the sufficient effects of the Use of drugs in the prevention of acute pancreatitis after ERCP compared to the stenting method combined with drug prevention in patients, although the results of this study should be confirmed by more extensive studies [41].

Post-ERCP problems in LT patients are notably mentioned in research by Domingo Balderramo. These results imply that post-ERCP problems were 9% in a cohort of LT patients treated at a sizable tertiary facility [7]. The incidence of pancreatitis is different in studies. The reason is due to the difference in the target groups.

PSP and ENBD are regarded as having the most efficacy in avoiding PEP among the analyzed studies and concentrated on procedural procedures. All patients with high risks should have PSP and ENBD, and individuals with moderate risks should also be considered. These methods can help with challenging and unsuccessful cannulation instances. Because PEP is introduced by a complex method, prevention of PEP may be unsuccessful if only one causal component is addressed. Through careful patient selection, the administration of pharmacologic prophylactic drugs, and procedural methods, the combination of numerous therapies may be more successful.

Further research is necessary to combine the prophylactic effects of these interventional strategies on preventing PEP. Future studies should concentrate on completing meta-analyses to obtain the pooled effect and overcome heterogeneity, imprecision, and the danger of publication bias. By doing so, the evaluation of the evidence‘s quality gleaned from research in the literature may be improved [42,43].

Although ERCP is a relatively safe procedure for diagnosing and treating diseases of the pancreatobiliary system, it can potentially cause severe and fatal complications. The most important complications of ERCP include pancreatitis, hemorrhage, infection, and perforation. A significant risk factor in the occurrence of the mentioned side effects has been identified, and the occurrence of the mentioned side effects can be prevented to a large extent by paying attention to them. The Use of alternative methods, such as MRCP or endosono graphy, should be considered in doubtful cases. Coagulation disorders often cause bleeding secondary to ERCP in patients. Balloon dilatation can be considered an alternative to sphincterotomy. Infections caused after ERCP are seen more in the presence of insufficient drainage and malignant obstructions. However, antibio tics are still not recommended as prophylaxis in all patients.

Nevertheless, it should be considered in high-risk patients. The issue seen in all the studies is work experience and another critical expertise of the person performing it, so people who do less than one operation per week have a higher probability of complications in patients. The most frequent ERCP consequence is pancreatitis, which necessitates hospitalization. Several pharmacological and procedure-related therapies have been researched to prevent this complication, yet the morbidity connected to ERCP still exists in large amounts. Careful patient selection and the early detection of risk factors are the most efficient ways to stop post-ERCP pancreatitis.