Precise Endoscopic Application of Nitroglycerin in Preventing Post-ERCP Pancreatitis

Endoscopic retrograde cholangiopancreatography (ERCP) is a complex procedure that combines endoscopy and fluoroscopy for the diagnosis and treatment of pancreaticobiliary ductal disorders, such as choledocholithiasis (bile duct stones), biliary strictures, and cholangitis (bile duct inflammation). Although ERCP is vital for both diagnosis and treatment, it carries a higher risk of complications than do other endoscopic procedures. Common complications include post-ERCP pancreatitis (PEP), bleeding, perforation, and biliary tract infections. The overall incidence rate of ERCP-associated complications is approximately 10%, with severe complications occurring in about 24% of patients who experience any complications. The rate of ERCP-associated mortality ranges from 0.2% to 0.7%. Despite technological advancements and enhanced safety protocols, the rate of ERCP-associated complications remains high.

Among all complications, post-ERCP pancreatitis presents a major challenge for clinicians and endoscopists. PEP increased hospitalization interval and mortality. While most cases of PEP are mild and resolve with conservative treatment, it can be dangerous in severe cases, such as pancreatic necrosis, multi-organ failure, and peripancreatic fluid collections. These complications are rare but can be fatal. The incidence rate of PEP varies depending on the patient population and risk factors. Generally, the overall incidence of PEP is reported to be between 2% and 10% in unselected patient samples. However, in high-risk patients, this rate can increase significantly, ranging from 8% to 40% or even higher. High-risk patients for post-ERCP pancreatitis include several groups based on both patient-related and procedure-related factors. Patient-related risk factors include female gender, younger patients under 50 years old, history of pancreatitis, and sphincter of Oddi dysfunction. Procedure-related risk factors include difficult biliary cannulation, precut papillotomy, and pancreatic duct cannulation.

Preventing PEP involves several strategies that can be implemented before, during, and after the procedure. Rectal nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin or diclofenac, should be administered immediately before ERCP to reduce the risk of PEP. High-volume intravenous fluids should be administered peri-procedurally to help prevent PEP. For high-risk patients with sphincter of Oddi dysfunction, difficult cannulation, or when the pancreatic duct is accessed repeatedly, prophylactic pancreatic stent placement during the procedure can reduce the risk of PEP.

Despite these preventing strategies, some patients still suffer from PEP. Additionally, patients with chronic kidney disease are contraindicated from NSAIDs. Instead, nitroglycerin has been shown to have a significant benefit in preventing PEP. Nitroglycerin plays a crucial role in managing angina pectoris for decades. Nitroglycerin affects smooth muscle primarily through its conversion to nitric oxide, which acts as a potent vasodilator. Nitric oxide activates the enzyme guanylate cyclase, which converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), leading to protein kinase-dependent phosphorylation and activation of downstream cascades that promote relaxation of smooth muscle cells. Pancreatic sphincter hypertension increases the risk of PEP. In this situation, nitroglycerin could lower the basal pressure in the sphincter of Oddi and depress the resistance of bile outflow, which may be potential in preventing PEP.

Previous clinical trial demonstrated that 15mg transdermal nitroglycerin patch protects against post-ERCP pancreatitis. Another clinical trial revealed that 5 mg sublingual nitroglycerin 5 minutes before ERCP could reduce pancreatitis and hyperamylasemia. The combination use of rectal indomethacin and 0.5 mg sublingual nitroglycerin can also prevent and relieve the severity of PEP after ERCP in patients with difficult cannulation. Systemic review and meta-analysis studies confirmed that patients who received nitroglycerin were 39 % less likely to develop pancreatitis, suggesting that nitroglycerin administered by the sublingual or transdermal route may be useful. However, current guideline doesn't suggest routine use of nitroglycerin due to inadequate evidence of benefits.

In order to enhance the smooth muscle relaxation without inducing systemic adverse events, topical administration of nitroglycerin can be a good solution. Topical nitroglycerin has shown benefits in reducing the anal tone for patients with Levator ani syndrome. Topical nitroglycerin also demonstrated effects in relieving pain for patients with anal fissure. Reducing sphincter spasm could also reduce post-hemorrhoidectomy pain. From above evidence, topical administration of nitroglycerin has shown local effect of smooth muscle relaxation, which may be beneficial in reducing the PEP rate or severity. This study aimed to investigate whether topical delivery of nitroglycerin can reduce the incidence rate of PEP or the severity of pancreatitis.

Study design and rationale Participants will be recruited from the volunteers with choledocholithiasis at National Cheng Kung University Hospital. Eligible participants include patients aged ≥ 18 years who accept ERCP and sphincterotomy for common bile duct (CBD) stone extraction. Patient consent forms will be given and explained to all patients before the ERCP. Exclusion criteria include patients with pancreatic cancer, shock status (systolic blood pressure \< 90 mmHg or using inotropic agents), allergy to NTG, angle-closure glaucoma, severe anemia, and patients on PDE 5 inhibitors. After patient enrollment, investigators will randomize the patient into either the intervention group or control group by sealed envelope randomization method.

All patients without chronic kidney disease (serum creatine \> 1.5 mg/dL) will receive rectal diclofenac 100 mg before the procedure. During the biliary cannulation, if twice or more times of pancreatic duct cannulation, a pancreatic plastic stent will be placed. Lactate ringer hydration will be provided to patients with pancreatic duct cannulation for 24 hours. After the EST and stone extraction, investigators will randomly assign the patients to either a control or an intervention group. After EST, if immediate bleeding occurs, investigators will apply standard endoscopic therapy by either local injection of diluted epinephrine or heater probe coagulation. Before the end of the exam, diluted 1mg nitroglycerin in normal saline (1mg/10cc) will be delivered to the major papilla in the intervention group.

Blood tests A blood sample is obtained as ward routine to measure creatinine, albumin, total bilirubin, hemoglobin, lipase, platelet, prothrombin time (PT), and activated partial thromboplastin time (APTT). All lab data are checked by the central laboratory of the National Cheng Kung University Hospital.

Outcome measures All patients will be monitored for 14 days after the ERCP. The primary endpoint is the incidence rate of post-ERCP pancreatitis, which is defined as epigastric pancreatic pain with elevated serum lipase over 200 U/L. The secondary endpoints include (1) the level of serum lipase the day after ERCP; (2) length of hospitalization; (3) all-cause mortality.

Statistical analysis According to previous literature, investigators set the event rate of PEP is 20 % and the delivery of nitroglycerin can reduce the PEP rate to 10%. Investigators need to enroll 199 patients at least in each group to reject the null hypothesis that the effects are equal between the two groups with the probabilities of power at 0.8 and type I error at 0.05. Assuming a drop rate of 10%, this study will enroll a total of 440 patients, including 220 patients in the intervention group and 220 patients in the control group, respectively. Data related to baseline characteristics and the endpoints are evaluated using the Student's test, Pearson's χ2 test or Fisher's exact test, and the Mann-Whitney U test. All tests are two-tailed and P-values \< 0.05 indicated significant differences.

• Occurence of moderate or severe PEP [Time frame: 7 days]
• Occurrence of post-ERCP bleeding [Time frame: 14 days]
• Occurrence of shock status [Time frame: 1 day]
• Length of hospitalization [Time frame: 14 days]
• Level of pancreatic serology [Time frame: 8 hours]