A systematic review and meta-analysis to study the effect of aggressive hydration with lactated ringer in preventing post-ERCP pancreatitis.

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis can be prevented with lactated ringer solution (LRS) hydration during the perioperative period of ERCP. 

With the rapid advancement of endoscopic technology, ERCP has become the standard methodology for endoscopic minimally invasive diagnosis and management of pancreatic and biliary disorders.  ERCP is extensively utilized in medical care practice and involves insertion of endoscopy in duodenum lower part and injecting contrast agent into the pancreaticobiliary duct. Though this procedure is considered to be safe, it may cause considerable complications in endoscopic surgery. Post-ERCP pancreatitis is the most commonly reported complication.

The mechanisms of pancreatic injury during ERCP include microbial, chemical, mechanical, enzymatic, thermal, and hydrostatic damage. Ampullary or duct impairment can be triggered by long-term surgery of papillary foramen, cannulation of the biliary tree and repeated cannulation. Thermal injury may result from electric knife current utilized in sphincterotomy (pancreatic or biliary), endoscopic papillectomy or ablation of tumors in Vater ampulla. Papillary edema, as a result of mechanical or thermal injury, seems to impede the outflow of pancreatic secretions, thus causing pancreatitis. Contrast agents may also cause post-ERCP pancreatitis by inducing chemical damage but, the data is still controversial.

In post-ERCP pancreatitis, the pancreatitis-associated clinical symptoms last for more than 24  hours after ERCP. Also, there is a rise in the levels of serum amylase (3 times greater than the upper limit of normal value). It is also known as hyperamylasemia after ERCP if there is only a rise in amylase after ERCP without any clinical manifestation of pancreatitis. Numerous factors such as procedure-related factors, patient-related factors, and endoscopist-related factors raise the risk of post-ERCP pancreatitis. Thus, chemical prevention and procedural techniques to prevent post-ERCP pancreatitis should consider all these factors.

Most complications are mild to moderate, few are serious and even can cause death. In clinical research, the prevention of post-ERCP pancreatitis is a crucial topic. The risk of post-ERCP pancreatitis in high and low-risk patients was greater than 16% and 5%, respectively. For reducing the risk, doctors must choose suitable patients, utilize ERCP almost exclusively as a therapy procedure, use valid procedural techniques, and consider the usage of active hydration, rectal indomethacin, or placement of pancreatic stents.

There is a requisition of large randomized controlled trials (RCTs) to examine further which group of patients benefit from rectal indomethacin therapy. Also, the role of pancreatic duct stenting in low-risk individuals needs to be assessed. Although numerous studies are available on preventive drugs for post-ERCP pancreatitis, however, the conclusions are inconsistent. In medical care practice, no unified post-ERCP pancreatitis drug prevention standard exists. The best prophylactic agents should be effective, easily accessible, have reduced adverse effects, high cost-benefit ratio, and convenient administration.

Currently, the guidewire-assisted cannulation technique and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for preventing post-ERCP pancreatitis. However, as per the systematic review, protecting pancreatic duct stent implantation might be limited to individuals having moderate but non-severe post-ERCP pancreatitis. Infusion therapy for pancreatitis has attracted extensive attention in recent years. Fluid therapy is a vital part of early therapy of acute pancreatitis. It minimizes hypovolemic shock that is usually linked with acute pancreatitis, enhances pancreatic microvascular perfusion, and thus enhances the prognosis of patients.

RATIONALE BEHIND RESEARCH

The optimal time, effects, and volume of fluid therapy are not certain in clinical acute pancreatitis. Taking into account some contraindications, studies with larger sample size are required to determine preventive effect of LRS on post-ERCP pancreatitis. Therefore, this study was conducted.

OBJECTIVE

This systematic review and meta-analysis was carried out to assess if aggressive hydration with LRS minimizes the incidence of PEP.

Literature search

Databases such as Cochrane Library, Scopus database, PubMed, China National Knowledge Infrastructure (CNKI), Web of Science, WanFang Data, Embase, and CQVIP were comprehensively searched to explore the suitable articles published before April 2019. The reference list of each article,  reviews and meta-analyses were also explored.

Inclusion criteria

Studies were incorporated in this study if:

• they were RCTs carried out in adults who were given ERCP procedures for any reason
• they were RCTs exploring aggressive hydration with LRS versus standard hydration on post-ERCP pancreatitis prophylaxis.
• the definition of post-ERCP pancreatitis was based on the consensus criteria as follows: levels of amylase in serum were three times greater than the upper normal limit at 24 hours following operation and the presence of continuous pancreatitis-like abdominal pain.
• the major outcome was defined as the occurrence of post-ERCP pancreatitis, whereas the secondary outcomes were defined as the occurrence of hyperamylasemia and the occurrence of side effects.

Exclusion criteria

Studies were excluded if they were:

• Non randomized studies
• Duplicate publications
• Including past ERCP history and combination of other pancreatitis prevention methods (NSAIDs and pancreatic duct stent)

Study selection and Data extraction

Two investigators screened the flow diagram and completed the extraction of data. The data extraction items included: sample size, post-ERCP pancreatitis diagnostic criteria, primary author, publication year, intervention, post-ERCP pancreatitis rate, hyperamylasemia rate, and rate of side effects in each study.

Data and Statistical Analysis

For the meta-analysis, Review Manager 5.3 and Stata 12.0 software were utilized. Statistical link between infusion and post-ERCP pancreatitis, and heterogeneity of studies were determined using 95% confidence intervals (CI) and pooled odds ratio (OR). Using the same, the forest plot was generated.

Chi-square based Cochrane Q statistic and the I² statistic was used to quantify heterogeneity. This statistic provides results ranging from 0 to 100%. If heterogeneity existed, the random-effects model was utilized instead of the fixed-effects model.

Furthermore, the factors influencing heterogeneity were examined. For testing the robustness of the overall assessment, sensitivity analyses were utilized. The publication bias was evaluated via visual inspection of the funnel plot. Subgroup assessments were carried out when heterogeneity was present.

Risk of Bias and Quality assessment

Assessment of the methodological quality of the studies was carried out as per the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. For comprehensively assessing this meta-analysis and guide clinical practice, the quality of evidence was determined with the aid of GRADE pro software. The domains that were considered to determine the risk of bias in this meta-analysis included  incomplete outcome data, allocation concealment, sequence generation, blinding of  personnel and participants, blinding of outcome assessment, selective reporting and other bias.

Two researchers determined the quality of evidence as per the GRADE quality assessment criteria. Disagreements were resolved by discussing or presenting to the third investigator for consultation. The quality of evidence falls into the following four categories: very low, low, moderate, or high.

Study outcomes

• The major outcome was the occurrence of post-ERCP pancreatitis.
• Secondary outcomes incorporated the occurrence of hyperamylasemia, adverse events, and abdominal pain.

Outcomes

Study and participant characteristics:

• Ten RCTs were incorporated in this study. Five of ten RCTs were published as full-text articles, 4 RCTs were published as abstract, and one study was available at Clinicaltrials.gov
• No profound differences existed between the groups regarding causes of obstruction, procedural time, trials of cannulation, single or many operators in each study, unintentional cannulation or contrasting of the pancreatic duct.

Study quality:

• Among 10 RCTs, six studies illustrated detailed data in allocation sequence generation.
• Notably, four studies did not offer complete data about the way of the allocation sequence generation.
• Five studies did not yield sufficient information about the allocation concealment method, while another five studies offered complete data in the allocation concealment method.
• Overall, four studies were single-blinded studies, and four studies were double-blinded studies.

Effect of intervention on the outcome:

• In comparison with standard hydration, aggressive hydration minimized the occurrence of post-ERCP pancreatitis (odds ratio [OR], 0.40) and hyperamylasemia after ERCP (OR, 0.48).
• Profound differences were witnessed between standard and aggressive hydration in the incidence of abdominal pain (OR, 0.29).
• No differences were noted in noxious events between standard and aggressive hydration (OR, 0.93).
• Sensitivity assessment demonstrated that neither alternative effect measures nor statistical models regarding heterogeneity influenced the study's conclusions.

In this study, ten RCTs, including 2200 people, were reviewed. It was found that people receiving aggressive hydration with LRS had a reduced risk of post-ERCP pancreatitis vs people receiving standard hydration during or after ERCP. Also, the occurrence of post-ERCP hyperamylasemia and abdominal pain declined with aggressive hydration. No vital differences were witnessed in the length of stay and adverse events between both the groups. But, the studies incorporated in this meta-analysis only used LRS. Therefore, the conclusion could not be applied to any other kind of liquid. Also, the total dosage of liquid therapy might matter.

The perioperative infusion of LRS was found to vary in different RCTs. For a 75 kg patient undergoing one hour ERCP, the fluid infusion doses were therefore estimated during and eight hours after ERCP. The onset of fluid therapy plays an essential role in influencing the occurrence of post-ERCP pancreatitis in this study. For preventing post-ERCP pancreatitis, it is suggested to use aggressive hydration with LRS. The results displayed similarity to the previous two published meta-analyses.

In this meta-analysis, more large-scale studies were incorporated, conclusions are more credible, and the quality of the evidence is much improved. A novel meta-analysis published in Pancreatology yielded the same conclusion. Since the type of actively hydrated fluid and the time and amount of infusion might influence the outcome of fluid resuscitation, a subgroup assessment was carried out. It was noted that initiating active LRS infusion during ERCP considerably minimized the occurrence of post-ERCP pancreatitis.

Improved perioperative fluid resuscitation can suppress pancreatic inflammation by maintaining pancreatic microcirculation. In ERCP people, relative dehydration may worsen microcirculation disturbance. The indirect proof favoring this theory is that the presurgery rise of blood urea nitrogen levels, as an assessment of hydration status, is related to post-ERCP pancreatitis. An early massive infusion may cause replenishment of blood circulation in time, prevent insufficient blood circulation caused by fasting water prior to ERCP, thus ensuring pancreatic blood perfusion.

This, in turn, lowers pancreatic hypoxia and ischemia, prevents calcium ions from entering pancreatic cells, minimizes pancreatic cell function impairment and pancreatic enzyme activation, and disrupts cascade waterfalls triggered by inflammatory factors. The cloth effect declines the level of amylase in serum and the incidence of post-ERCP pancreatitis after ERCP. In comparison with normal saline, LRS can minimize the occurrence of metabolic acidosis and systemic inflammatory response syndrome. LRS can also elicit anti-allergic reactions. Previous prevention of post-ERCP pancreatitis was primarily concentrated in the rectum. NSAIDs and pancreatic stent implantation were advocated.

In the past few years, the prevention of post-ERCP pancreatitis by LRS during the perioperative period has been given greater attention. This study majorly discusses the preventive effect of LRS on post-ERCP pancreatitis. LRS is inexpensive, widely available, safe, and not easily damaged. Infusion of this solution is a convenient and simple way for preventing post-ERCP pancreatitis that can be utilized as a supplement for preventing post-ERCP pancreatitis, at least in clinical practice.