1. IntroductionEndoscopic retrograde cholangio-pancreatography (ERCP) is an important procedure to diagnose and treat hepatobiliary and pancreatic diseases. Pancreatitis is one of the most common and severe complications after ERCP, with the reported incidence ranging from 3.47% to 9.70% in recent studies [1,2]. The generally accepted definition of post-ERCP pancreatitis (PEP) was advanced by Cotton et al. in 1991 [3], which included the new or exacerbating pancreatic-type abdominal pain, accompanied by serum amylase exceeding at least three times the upper limit of the normal value occurring within 24 h post-ERCP, as well as hospital admission duration for more than one day. The severity of PEP was also defined according to the consensus criteria, which is shown in Table 1. In addition, Banks et al. [4] proposed the classification of acute pancreatitis which was used in some studies. Although differences in the criteria for defining PEP and severity classification are likely to influence the reported rates, the majority of PEP is assumed to be mild. In contrast, severe pancreatitis has a lower incidence, but still is a major contributing factor in the death of patients.The majority of relevant references in this review use the Cotton et al. consensus to define PEP. The mechanism of post-ERCP pancreatitis (PEP) is still unclear, which could be associated with mechanical injury, thermal injury, chemical or allergic injury, etc. These factors activate proteolytic enzymes within acinar cells, ultimately leading to cellular injury and autodigestion of the pancreas [5]. Recently, various research is being conducted to explain the mechanism and etiologies of PEP. This review mainly introduces the precautionary measures to prevent PEP. 2. Risk FactorsThe risk factors related to PEP have been investigated in many studies and systematic reviews, and some patient-related risk factors (e.g., female, previous PEP, previous pancreatitis, and sphincter of Oddi dysfunction) and procedure-related risk factors (e.g., difficult cannulation, pancreatic injection, precut sphincterotomy, and non-prophylactic pancreatic duct stent) have been confirmed [6,7,8,9,10,11]. The presence of multiple factors can have a cumulative effect. Typically, patients without the above risk factors were defined as low-risk. High-risk patients were identified as patients who met one or more of the above risk factors factors [12]. In addition, there are a number of other risk factors that we need to consider, for example the research of Deenadayalu VP et al. showed that obesity increases the risk of PEP (OR = 1.143; p = 0.002) [13], and other earlier studies also found that using pancreatotoxic drugs (including estrogen, azathioprine, valproic acid, mesalazine, morphine derivatives, and prednisone) in the preoperative period of ERCP significantly increased the risk of PEP (OR = 3.7, p = 0.04) [14]. However, the use of BMI and drugs is not involved in the recent meta-analysis because of the lack of relevant clinical studies. In addition, several studies [15,16,17] have shown that the incidence of PEP progressively decreases with age and middle-aged people have a higher incidence and mortality. The pathophysiology behind that observance remains unclear. One explanation could be reduced levels of pancreatic enzyme secretion or more advanced atrophy of the pancreas in older patients [16,17].Because of the high incidence of PEP in high-risk patients, early identification and the implementation of therapeutic strategies for high-risk patients is critical to avoid the occurrence of PEP [18,19]. Additionally, further investigations of novel risk factors of PEP are highly warranted. The risk factors of PEP are shown in Table 2. 4. Combined Prevention

Combined prevention has actually been extensively used in high-risk patients. Clinicians generally use rectal NSAIDs and prophylactic pancreatic stenting to prevent PEP in high-risk patients, and the treatment effect is obvious. However, for low-risk patients, prophylactic pancreatic stenting is not an efficient and cost-effective approach. Therefore, we think that PEP-related risk factors should be used to stratify risk among patients better before the procedure, which would help physicians decide on preventative measures, such as drug prophylaxis or PD stenting.

For low-risk patients, clinicians emphasize the use of pharmacological treatment to prevent PEP, which is generally accepted for their obvious advantages such as good efficacy and a cheaper price. Based on the current research, we found that the use of rectal NSAIDs alone cannot completely prevent PEP and the use of other drugs only, such as GTN and somatostatin/ octreotide, also have some limitations. Thus, we suggest the combination of multiple drugs to prevent PEP in low-risk patients.

So far, the combined prevention of multiple drugs has shown effective results in the latest clinical trials, which is a good start. The result confirms further investigations are worthy and needed. In 2014, Sotoudehmanesh et al. [127] performed a randomized, double-blind controlled trial (300 patients) to evaluate the efficacy of the combination of indomethacin and sublingual nitrates compared with indomethacin alone to prevent PEP. The experimental results were pleasantly surprising. Rectal indomethacin plus sublingual nitrate significantly reduced the incidence of PEP compared with indomethacin alone (6.7% vs. 15.3%, RR = 0.39, 95% CI: 0.18–0.86, p = 0.016). In addition, adding drugs did not increase drug-related adverse effects. The latest trial [128] (886 patients) obtained similar results that rectal diclofenac plus sublingual nitrate significantly reduced the incidence of PEP compared with diclofenac alone (5.6% vs. 9.5%, RR = 0.59, 95% CI: 0.37–0.95, p = 0.03). Although some patients developed hypotension and headache in the combined group, they were significantly relieved after simple treatment. Furthermore, the relative benefit of additional sublingual nitrate had a tendency to decline according to the number of risk factors for PEP. Due to it being simple, inexpensive, and well tolerated, the combination of rectally administered NSAIDs and sublingual nitrate should be an ideal pharmacologic prophylaxis in low-risk patients (moderate quality evidence). In addition, there are other drug combinations being studied. The study of Katsinelos et al. [129] (540 patients) demonstrated that the preventive effect of rectal diclofenac plus somatostatin was better than that of rectal diclofenac alone (low quality evidence). In the multivariate analysis, pretreatment with diclofenac plus somatostatin significantly reduced the risk of PEP (OR = 0.423, 95% CI: 0.201–0.889, p = 0.023). Hajalikhani et al. [130] compared the preventive effects of diclofenac and aggressive hydration by LR (n = 107) with diclofenac alone (n = 112). Although the results showed that there was no significant difference between them (0.9% vs. 2.7%, p = 0.622), the serum levels of pancreatic enzymes in the combination group were significantly lower than those of diclofenac alone group at 2 h, 8 h, and 24 h after ERCP (p131] (192 high risk patients) showed that LR plus indomethacin had a lower PEP rate (6% vs. 21%, p = 0.04) and a lower readmission rate (2% vs. 13%; p = 0.03) compared with normal saline plus placebo. Although these results cannot confirm the superiority of NSAIDs plus LR, they showed that the combination of NSAIDs and aggressive hydration to prevent PEP is feasible. Excitingly, the latest network meta-analysis [132] (24 studies, 11,321 patients) showed that indomethacin plus LR solution, followed by diclofenac plus nitrate and indomethacin plus normal saline, are the most efficacious combinations of pharmacological agents for the prevention of PEP (low quality evidence). These experimental results undoubtedly bring confidence to the combination of drugs to prevent PEP. However, it is not the case that increasing the type of drug use can greatly improve the preventive effect. For example, a latest meta-analysis of rectal indomethacin plus topical epinephrine to prevent PEP (3 RCTs, 2244 patients) showed that this combination had no more advantage than rectal indomethacin alone (RR = 1.15, 95% CI: 0.62–2.2) [133]. This is an indication that the combination of drugs to prevent PEP is not simply adding drugs to improve the preventive effect. There are many questions to be considered in combined prevention, including which drugs should be combined, whether the dose of combined drug should be changed, whether the adverse drug reactions of the combined drug are obvious, etc. At present, there are few large-scale clinical trials in this area, and we hope that more large-sample studies can be published. Clinically, effective drug combinations use are worthy of promotion in low-risk patients.For high-risk patients, factors that promote the occurrence of PEP are diverse and complex, combining drugs with mechanical prophylaxis to prevent PEP in high-risk patients is necessary, with PD stenting being the recommended option (Table 4).

At present, the most commonly used mechanical prophylaxis to prevent PEP in high-risk patients is PD stenting, which is recommended in most patients with difficult cannulation, suspected sphincter dysfunction, history of post-ERCP pancreatitis, or in those with other risk factors. Most of the studies of PD stenting to prevent PEP were conducted before the routine use of pharmacological prophylaxis including indomethacin (high quality evidence). In addition to this, an atraumatic and efficient method of cannulation needs to be used in difficult intubation cases, such as the WGC technique, TPS, or needle-knife precut sphincterotomy. Until further evidence are available, it is advisable to combine pharmacological with mechanical prophylaxis in high-risk cases (moderate quality evidence).