Precise Endoscopic Application of Nitroglycerin in Preventing Post-ERCP Pancreatitis: A Randomized Controlled Trial

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.