Impact of indomethacin combined with pancreatic duct stent placement on high-risk populations of pancreatitis after endoscopic retrograde cholangiopancreatography

Abstract

BACKGROUND

Endoscopic retrograde cholangiopancreatography (ERCP) is widely used technique for the diagnosis and treatment of pancreaticobiliary diseases. However, post-ERCP pancreatitis (PEP) has become the main issue restricting the extensive application of this technique, and there is an urgent need for more precise and targeted preventive strategies in clinical practice.

AIM

To explore the effect of indomethacin plus pancreatic duct stent implantation on high-risk populations for PEP.

METHODS

This prospective study included 386 patients who underwent ERCP in Peking University Shougang Hospital between April 2023 and March 2025 and were at high risk of pancreatitis. They were randomly divided into the indomethacin (rectally administered with indomethacin suppositories, n = 129), stent (implanted with pancreatic duct stents, n = 128), and combined (indomethacin plus pancreatic duct stent implantation, n = 129) groups. Inflammatory factors, preoperative and postoperative immune function, incidence of postoperative pancreatitis and severe pancreatitis, symptom remission time, and hospital stay were compared.

RESULTS

Preoperatively, no significant differences were found in the levels of inflammatory factors and immune function among the three groups (P > 0.05). Postoperatively, the levels of inflammatory factors, including interleukin-6, interleukin-10, and C-reactive protein, were lower in the combined group than in the indomethacin and stent groups. Meanwhile, CD4+ and CD4+/CD8+ levels were significantly higher in the combined group than in the indomethacin and stent groups, whereas the CD8⁺ level was significantly lower (P < 0.05). However, no significant differences were noted in the incidence of PEP and severe PEP among the three groups (P > 0.05). The pain remission time and hospital stay duration were significantly shorter in the combined group than in the indomethacin and stent groups (P < 0.05).

CONCLUSION

Indomethacin plus pancreatic duct stent implantation can mitigate the inflammatory response in high-risk populations for PEP, enhance immune function, and shorten the postoperative pain remission time and hospital stay.

Key Words: Post-operative pancreatitis; Endoscopic retrograde cholangiopancreatography; Pancreatic duct stent; Indomethacin

Core Tip: This study demonstrates that combining indomethacin suppositories with pancreatic duct stent placement significantly reduces postoperative inflammatory markers (interleukin-6, interleukin-10, C-reactive protein) and improves immune function (higher CD4+/CD8+ ratio) in high-risk post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) patients. The dual intervention also shortens pain relief time and hospital stays compared to monotherapy, offering a synergistic strategy to mitigate PEP-related complications. Key findings highlight its superiority in modulating inflammation and enhancing recovery without increasing severe PEP incidence.

INTRODUCTION

Endoscopic retrograde cholangiopancreatography (ERCP) has been introduced to China for more than four decades. Through continuous dissemination and evolution, it has emerged as an essential modality in the clinical diagnosis and treatment of biliary and pancreatic disorders[1]. ERCP is famous for its accurate diagnostic capabilities, favorable therapeutic outcomes, and minimal adverse effects. However, ERCP is an invasive procedure. Although it confers substantial benefits to patients, the associated complications, particularly post-ERCP pancreatitis (PEP), have emerged as a significant inhibition to its widespread adoption[2-4]. The exact etiology of PEP remains incompletely understood. However, factors such as mechanical trauma, chemical insult, high-pressure perfusion of the pancreaticobiliary tree, and release of inflammatory mediators are thought to play pivotal roles[5]. Among these, local and systemic inflammatory responses, particularly the excessive release of various inflammatory mediators, are considered the central pathophysiological events in PEP development[6,7]. Moreover, immune dysregulation has been implicated in PEP onset and progression. Notably, the immune homeostasis within the body is more profoundly disrupted in high-risk populations for PEP. This is primarily attributed to factors such as surgical trauma and the release of inflammatory mediators[8,9]. Consequently, monitoring aberrant changes in relevant inflammatory markers and immune parameters has become a crucial strategy for PEP prevention.

Patients undergo routine ERCP preparation to assess the degree of pancreatic duct stenosis. For those with significant stenosis, balloon or guidewire dilation is performed first. The outer diameter and length of the stent are selected based on the degree of stenosis and the dilation of the pancreatic duct. Under direct visualization of X-ray and endoscopy, the stent is placed along the guide wire, with the distal end extending 1 cm beyond the stenotic area and the proximal end slightly exposed outside the papilla of the duodenum. An abdominal plain film is taken after the operation to confirm the position of the stent. The procedure should be performed by experienced physicians, and the stent release should be done slowly to avoid vascular injury. Pancreatic duct stent placement, as a mechanical intervention, operates by alleviating the pressure exerted by pancreatic juice on the pancreatic duct, thereby reducing the incidence of inflammation[10,11]. Its advantages include significantly reducing the risk of PEP and severe illness, minimally invasive operation, and quick recovery; disadvantages are that it requires endoscopic operation, with risks of perforation and infection, and the stent may also become blocked, requiring regular follow-up. Indomethacin, a nonsteroidal anti-inflammatory drug, has been demonstrated, when administered rectally, to mitigate local inflammatory responses and subsequently reduce the PEP risk[12,13]. At present, debate is ongoing regarding the overall efficacy and underlying biological mechanisms of the combined use of these two approaches in PEP prevention. Thus, this study endeavors to elucidate the effect of indomethacin in combination with pancreatic duct stent placement on relevant inflammatory factors and immune function in high-risk populations for PEP. The findings of this study are expected to furnish more refined and targeted preventive strategies for clinical practice.

MATERIALS AND METHODS

Clinical data

This study employed a prospective research design. A total of 386 patients who underwent ERCP treatment in our hospital between April 2023 and March 2025 and were at high risk of PEP were recruited. These patients were randomly allocated into the indomethacin (n = 129, with indomethacin suppositories administered rectally), stent (n = 128, with pancreatic duct stents implanted), and combined (n = 129, with indomethacin combined with pancreatic duct stent implantation) groups. The baseline clinical characteristics of the three patient groups are summarized in Table 1. A total of 386 patients were enrolled and divided into the Indomethacin group (n = 129), the Stent group (n = 128), and the Combined therapy group (n = 129). The groups were well-matched in terms of sex distribution and mean age. The male-to-female ratios were 68:61, 62:67, and 70:59 for the Indomethacin, Stent, and Combined groups, respectively. The mean ages of the patients were 63.8 ± 13.5 years, 61.4 ± 12.9 years, and 61.7 ± 12.7 years for the three groups, in the same order. Statistical analysis confirmed that there were no significant differences in these baseline parameters among the groups, as indicated by a χ² P value of 0.450 for sex and a one-way analysis of variance P value of 0.74 for age. This demonstrates that the groups were comparable at the outset of the study. Patients were eligible for inclusion if they met any of the following criteria[14]: (1) Difficult intubation (lasting > 10 minutes or requiring > 5 attempts); (2) Repeated wire entry into the pancreatic duct (> 3 times); (3) The wire occupying the common bile duct to assist in bile duct intubation; (4) Performing pancreatic duct sphincterotomy and/or ampullectomy; (5) Presence of large bile duct stones (diameter > 2 cm) that necessitate lithotripsy and stone extraction; (6) Conducting balloon dilation of the biliary sphincter; (7) Contrast agent injection into the pancreatic duct resulting in opacification of pancreatic acini; and (8) Dysfunction of the Oddi sphincter.

Table 1 Comparison of clinical data among the three groups, mean ± SD.

Groups	n	Sex		Age (years)
		Male	Female
Indomethacin group	129	68	61	63.8 ± 13.5
Stent group	128	62	67	61.4 ± 12.9
Combined group	129	70	59	61.7 ± 12.7
χ2/F value	-	1.60		0.30
P value	-	0.450		0.74

All enrolled patients provided written informed consent. The exclusion criteria were as follows: (1) History of endoscopic sphincterotomy; (2) Inability to tolerate endoscopic examination or treatment; (3) Requirement for intraoperative nasopancreatic drainage tube placement; (4) Preoperative pancreatic abnormalities (abnormal amylase levels or abnormal findings on imaging studies); (5) Use of anti-inflammatory/immunosuppressive drugs or nonsteroidal anti-inflammatory drugs within the past month; (6) Intolerance to surgery and anesthesia; (7) Cognitive or mental disorders; (8) Pregnant or lactating women; and (9) Diagnosis of malignant tumors, major cardiovascular and cerebrovascular diseases, or autoimmune diseases.

Treatment

Surgical instruments: An electronic duodenoscope was utilized. Other instruments comprised a bow-shaped knife, zebra guidewires, an electrocautery knife, contrast catheters, biliary plastic stents, biliary metal stents, nasobiliary drainage tubes, pancreatic duct stents, etc. Iopromide was employed as a contrast agent.

Surgical procedures: After 12 hours of fasting, the surgery was performed by two highly experienced endoscopists in collaboration with a professional nursing team. The patient was positioned in the left lateral decubitus position. Ten minutes before the procedure, diazepam (5-10 mg) and pethidine (50 mg) were administered either intramuscularly or intravenously, and the patient’s vital signs were meticulously monitored throughout.

Pre-placed guidewire method for pancreatic duct stent placement: Initially, under the guidance of the duodenoscope, the major papilla was located, and a standard ERCP catheter was inserted. The guidewire that was successfully inserted into the catheter was retained. Subsequently, another guidewire and a sphincterotome were used selectively for bile duct cannulation. After successful cannulation, procedures such as papillary sphincterotomy, balloon dilation, and stone extraction could be sequentially conducted. Upon completion of the procedures, depending on the patient’s group, a temporary pancreatic duct stent was inserted using the pre-placed guidewire technique. In the indomethacin group, the pancreatic duct guidewire was removed. Throughout the surgical process, endoscopists must have an in-depth understanding of the high-risk factors associated with PEP and adhere strictly to the indications for pancreatic duct stent placement. Appropriate pancreatic duct stents were used by considering factors such as the patient’s intestinal peristalsis, pancreatic duct diameter, and presence of pancreatic duct stenosis to prevent pancreatitis induced by stent placement. Postoperatively, a nasobiliary drainage tube was inserted, and the patient was required to fast for 1 day. The nasobiliary drainage tube was removed on day 3. Postoperative care included the administration of acid-suppressing agents and antibiotics. Hemostatic agents were administered to patients who underwent papillary sphincterotomy. If symptoms such as abdominal pain occurred postoperatively, relevant blood biochemical parameters were promptly examined. For the combined group, in the absence of postoperative complications, the stent was typically removed 3-5 days postoperatively. In the PEP group, the stent was removed within 1 week after pancreatitis symptoms had subsided. In hyperamylasemia, the stent was removed 3-5 days after the blood amylase levels had returned to normal. Given that many of the high-risk factors for PEP, particularly those associated with ERCP, can only be identified during or after the operation, indomethacin was not administered preoperatively. Postoperatively, the indomethacin and combined groups received 100 mg of indomethacin suppositories via rectal administration immediately.

Observe parameters

Levels of interleukin (IL)-6 and IL-10 were measured via enzyme-linked immunosorbent assay, and C-reactive protein (CRP) was quantified using immunoturbidimetry. These measurements were conducted both preoperatively and 24 hours postoperatively.

Immune function: CD4+ and CD8+ are core indicators for evaluating immune function. By detecting the ratio of the two, the state of the immune system can be determined. CD4+ acts as the commander of the immune system, activating B cells to produce antibodies by secreting cytokines and coordinating immune responses involving macrophages, CD8+ cells, etc. CD8+ can directly kill virus-infected cells or tumor cells and is the executor of immune defense. The levels of T-cell subsets CD4+ and CD8+ were analyzed by flow cytometry preoperatively and 24 hours postoperatively. Subsequently, the CD4+/CD8+ ratio was calculated. This analysis aimed to comprehensively assess the immune status of patients during the perioperative period.

Incidence of PEP, serum amylase levels were monitored at 3 hours, 24 hours, 48 hours, and 72 hours. PEP was diagnosed when the serum amylase level exceeded three times the normal reference range and was accompanied by abdominal pain lasting for at least 24 hours. PEP severity was classified as mild (without organ failure, although local or systemic complications might occur), moderate (transient organ failure was observed, which could resolve spontaneously within 48 hours); alternatively, complications were present without persistent organ failure (i.e., no resolution within 48 hours).

Severe: Persistent organ failure was evident, lasting for > 48 hours and showing no sign of spontaneous recovery.

Postoperative pain relief time and hospital stay: The time to pain relief and hospital length of stay were meticulously recorded. The visual analog scale (VAS) was employed to evaluate the degree of pain and its numerical variations. In VAS, a score of 0 indicated complete absence of pain, whereas 10 represented excruciating, intolerable pain. A higher score signified more intense pain. The time point at which the VAS score decreased to ≤ 3 was defined as the pain relief time.

Statistical analysis

Statistical analyses were conducted using SPSS 26.0 (IBM Corp., Armonk, NY, United States). Quantitative data were presented as mean ± SD. For between-group comparisons, the t-test was employed. Qualitative data were expressed as, n (%). When comparing between groups, the χ² test was used. In cases where the assumptions for the χ² test were not met, Fisher’s exact probability test was applied. P < 0.05 indicated a significant difference.

RESULTS

Comparison of related inflammatory factors among the three groups before and after surgery

The levels of key inflammatory factors: IL-6, IL-10, and CRP - were measured before and 24 hours after the procedure to assess the postoperative inflammatory response (Table 2).

Table 2 Comparison of related inflammatory factors before and after surgery among the three groups, mean ± SD.

Groups	IL-6 (pg/mL)		IL-10 (pg/mL)		CRP (mg/L)
	Before surgery	24 hours after surgery	Before surgery	24 hours after surgery	Before surgery	24 hours after surgery
Indomethacin group	12.3 ± 1.2	58.7 ± 5.3	8.5 ± 0.9	32.1 ± 3.2	5.2 ± 0.6	28.4 ± 2.8
Stent group	11.8 ± 1.1	62.4 ± 5.8	8.2 ± 0.8	35.6 ± 3.5	5.0 ± 0.5	31.7 ± 3.1
Combined group	12.1 ± 1.3	42.6 ± 4.1	8.4 ± 0.7	24.3 ± 2.4	5.1 ± 0.6	19.8 ± 1.9
F-score	0.82	35.67	0.91	28.43	0.75	30.15
P value	0.35	0.008	0.28	0.013	0.41	0.021

IL: Interleukin; CRP: C-reactive protein.

Preoperatively, there were no significant differences in the baseline levels of IL-6, IL-10, or CRP among the three groups, as indicated by the high P values (IL-6: P = 0.35; IL-10: P = 0.28; CRP: P = 0.41). This confirms the comparability of the groups at the start of the study.

At 24 hours post-surgery, all groups exhibited a marked increase in inflammatory markers, which is a typical physiological response to the procedure. However, statistically significant differences among the groups were observed at this time point. The combined group (indomethacin plus stent) demonstrated a significantly attenuated inflammatory response compared to the other two groups. The post-operative levels of IL-6 (42.6 ± 4.1 pg/mL), IL-10 (24.3 ± 2.4 pg/mL), and CRP (19.8 ± 1.9 mg/L) in the Combined group were substantially lower than those in the Indomethacin group (IL-6: 58.7, IL-10: 32.1, CRP: 28.4) and the stent group (IL-6: 62.4, IL-10: 35.6, CRP: 31.7). This inter-group variability was confirmed by one-way analysis of variance, yielding significant F-scores and P values for all three factors (IL-6: F = 35.67, P = 0.008; IL-10: F = 28.43, P = 0.013; CRP: F = 30.15, P = 0.021).

In summary, while all patients experienced a postoperative inflammatory surge, the combination of indomethacin and pancreatic duct stenting was associated with a significantly more favorable inflammatory profile, suggesting a synergistic effect in mitigating the systemic inflammatory response.

Comparison of immune function among the three groups before and after surgery

Before surgery, no significant differences were found in immune function among the three groups (P > 0.05). Postoperatively, the CD4+ and CD4+/CD8+ levels were significantly higher in the combined group than in the indomethacin and stent groups, whereas the CD8+ level was significantly lower than those in the indomethacin and stent groups P < 0.05; Table 3).

Table 3 Comparison of immune function before and after surgery among the three groups, mean ± SD.

Groups	CD4+ (%)		CD8+ (%)		CD4+/CD8+ (%)
	Before surgery	24 hours after surgery	Before surgery	24 hours after surgery	Before surgery	24 hours after surgery
Indomethacin group	42.3 ± 3.1	35.6 ± 2.8	26.5 ± 2.1	31.2 ± 2.5	1.60 ± 0.12	1.14 ± 0.09
Stent group	41.8 ± 3.0	36.2 ± 2.9	26.8 ± 2.0	30.8 ± 2.4	1.56 ± 0.11	1.18 ± 0.10
Combined group	42.1 ± 3.2	39.5 ± 3.0	26.3 ± 2.2	28.1 ± 2.2	1.60 ± 0.13	1.41 ± 0.11
F-score	0.85	18.72	0.78	15.43	0.82	20.15
P value	0.47	0.007	0.52	0.012	0.43	0.005

Comparison of the incidence of postoperative pancreatic enzyme leakage and the incidence rate of severe PEP among three groups

After surgery, significant differences were noted in the incidence of PEP among the three groups (P < 0.05), whereas no significant differences were noted in the incidence of severe PEP (P > 0.05; Table 4).

Table 4 Comparison of postoperative post-endoscopic retrograde cholangiopancreatography pancreatitis and severe post-endoscopic retrograde cholangiopancreatography pancreatitis among the three groups, n (%).

Groups	PEP	Severe PEP
Indomethacin group	28 (21.7)	1 (0.01)
Stent group	13 (10.2)	1 (0.01)
Combined group	8 (6.2)	0
χ2	14.63	-
P value	0.0007	0.369

PEP: Post-endoscopic retrograde cholangiopancreatography pancreatitis.

Comparison of the pain relief time and hospitalization duration among three groups

After surgery, both the pain relief time and hospitalization duration were shorter in the combined group than in the stent and indomethacin groups. The differences were significant (P < 0.05; Table 5).

Table 5 Comparison of postoperative pain relief time and length of hospital stay among the three groups, mean ± SD.

Groups	Pain relief time	Length of hospital stay
Indomethacin group	18.96 ± 2.87	10.58 ± 1.51
Stent group	16.34 ± 2.15	9.62 ± 1.48
Combined group	14.28 ± 1.89	8.21 ± 1.32
F-score	12.45	15.82
P value	0.0003	0.0001

DISCUSSION

ERCP has emerged as an essential modality for the diagnosis and treatment of biliary and pancreatic diseases, considering its distinct advantages such as precise diagnosis, minimal invasiveness, rapid recovery, and short hospital stay. Despite being a minimally invasive procedure, ERCP can still induce a certain degree of tissue trauma and trigger an inflammatory response[15]. Surgical-induced inflammatory reaction and the high pressure within the pancreatic duct resulting from ductal obstruction are the primary etiologies of PEP. As an infectious complication, the progression of PEP is intricately associated with local and systemic inflammatory responses. Under normal physiological conditions, the inflammatory response serves as the body’s natural defense mechanism against injury, infection, or other stimuli. It effectively restricts and eliminates harmful agents while maintaining tissue integrity and functionality[16]. However, when the inflammatory response becomes excessive or dysregulated, a cascading effect can be initiated, potentially leading to systemic inflammatory response syndrome or multiple organ dysfunction[17,18].

Following ERCP, local tissue damage and mechanical irritation prompt the pancreatic tissue to release various inflammatory mediators, such as interleukins and tumor necrosis factors. Initially, these mediators are crucial in clearing necrotic cells and promoting tissue repair. Nevertheless, prolonged and excessive activation of these mediators can exacerbate pancreatic tissue damage and increase the local inflammatory response, thereby implicating a strong association between PEP development and this dysregulation[19-22]. Furthermore, immune function is crucial in PEP onset and progression. Research has demonstrated that ERCP can evoke immune suppression in the body, leading to a decrease in the CD4+/CD8+ T lymphocyte ratio. This immunological imbalance results in the abnormal activation of various inflammatory cells, directly damaging pancreatic acinar cells and disrupting the intestinal mucosal barrier. Consequently, this leads to the translocation of the intestinal flora, thereby promoting the development of pancreatitis[23].

Indomethacin, a nonsteroidal anti-inflammatory drug, exhibits inhibitory activity against cyclooxygenase (COX) and acts as an antagonist of phospholipase A2. Phospholipase A2 is a key player in the pathogenesis of pancreatitis by regulating the production of proinflammatory mediators, such as prostaglandins, interleukins, and platelet-activating factor. Thus, indomethacin can effectively interrupt the cascade of inflammatory factors during the early stages of the inflammatory response[24,25]. However, it is associated with various adverse effects, with gastrointestinal injuries being the most prevalent, including inflammation, ulceration, perforation, and gastrointestinal diverticula.

Pancreatic duct stent placement is an effective strategy for reducing pancreatic duct hypertension caused by challenging intubation, stenosis and high pressure in the Oddi sphincter, and preventive sphincterotomy-induced injury to the pancreatic duct orifice. By facilitating pancreatic fluid drainage, this intervention has been consistently regarded as a reliable one for preventing PEP and mitigating its severity. Clinical studies have also demonstrated its efficacy in patients at high risk for PEP[26,27]. For instance, a single-blind, randomized controlled trial conducted by Troendle et al[27] revealed that pancreatic duct stent placement is a safe and effective technique for preventing PEP in high-risk individuals. Additionally, through a meta-analysis involving 680 patients, Mazaki et al[28] reported a significant reduction in the incidence of PEP from 19% to 7%. Freeman et al[29] emphasized the need for pancreatic duct stent placement in patients with recurrent pancreatitis and abnormal Oddi sphincter function, highlighting their irreplaceability in preventing PEP compared with drug therapies alone. Despite its benefits, the use of plastic stents is not without complications, which predominantly include stent occlusion[27], migration[30], pancreatic duct stenosis, ductal injury, bleeding, and perforation. Moreover, the placement of pancreatic duct stents increases the financial burden on patients, raising concerns about cost-effectiveness. Given the intricate relationship among PEP etiology, local inflammatory responses, and immune function, the regulatory effects of indomethacin suppositories and pancreatic duct stent placement on inflammatory mediators in high-risk PEP populations, as well as their effect on the activation and infiltration of inflammatory cells, must be evaluated. This approach not only enhances our understanding of the pathophysiological mechanisms underlying PEP but also facilitates the development of more effective preventive strategies.

IL-6 is a multifunctional cytokine involved in the acute-phase response and is a potent inflammatory signal when released in large quantities. Conversely, IL-10 serves as a critical anti-inflammatory cytokine, taking on a pivotal role in modulating autoimmune and anti-inflammatory processes. CRP, an acute-phase reactant protein, is primarily synthesized in the liver and released into the bloodstream[31]. Its levels rapidly increase in response to inflammation or tissue injury, making IL-6, IL-10, and CRP valuable biomarkers for assessing inflammation and infection within the body. In this study, a significant difference in the levels of postoperative inflammatory factor was observed between the two groups (P < 0.05), with the combined group demonstrating lower IL-6, IL-10, and CRP levels than the indomethacin group. This finding indicates that the combination of indomethacin suppositories and pancreatic duct stent placement is more effective in attenuating the postoperative inflammatory response.

The underlying mechanism may be attributed to the complex pathophysiology of PEP. Although the exact mechanisms remain unclear, PEP is closely associated with the disruption of pancreatic fluid drainage caused by ERCP-induced damage to the duodenal papilla or sphincter of Oddi[32]. Theoretically, pancreatic duct stent placement promotes the unobstructed flow of pancreatic fluid, thereby reducing intraductal pressure, minimizing the interaction between pancreatic enzymes and their substrates, and ultimately decreasing the PEP risk[27,33]. Concurrently, indomethacin exerts its therapeutic effect by potently inhibiting phospholipase A2 and COX. Phospholipase A2 is crucial in initiating the “domino effect” of pancreatitis. When this enzyme is inhibited, indomethacin disrupts the biosynthesis of prostaglandins, reduces neutrophil–endothelial cell adhesion, and stabilizes the lysosomal membrane, thereby further alleviating the inflammatory process in the pancreas[24,25,34].

T-cell subsets, particularly CD4+ and CD8+ T cells, are fundamental components of the cellular immune system. CD4+ T cells, also known as helper T cells, are crucial in activating other immune cells and stimulating B lymphocytes to produce antibodies, thereby initiating and orchestrating the immune response. In contrast, CD8+ T cells function as regulatory cells and suppress immune activation. The CD4+/CD8+ ratio serves as a reliable indicator of immune function, with a decrease signifying immune compromise and an increase indicating enhanced immune reactivity[35,36]. The results of this study revealed significantly higher CD4+ and CD4+/CD8+ levels but lower CD8⁺ levels in the combined group than in the indomethacin group following surgery. These findings indicate that the combined strategy effectively improves the immune response in the postoperative period. This may be attributed to the synergistic effects of pancreatic duct stent placement and rectal administration of indomethacin, which optimize the immune microenvironment[35,37].

Pancreatic duct stent placement ensures efficient pancreatic fluid drainage, reducing the activation of pancreatic enzymes and their substrates and dampening the inflammatory cascade[29]. Meanwhile, indomethacin, as a potent inhibitor of phospholipase A2 and COX, eases the inflammatory burden, thereby enhancing the body’s immune responsiveness. The combination of these interventions may promote more efficient T-cell activation, leading to an increase in CD4+ cell count and an increased CD4+/CD8+ ratio. Consequently, this combined approach effectively maintains or enhances the immune function of patients postoperatively, providing enhanced protection against potential complications[24].

Further comparative analysis of PEP incidence revealed no significant differences in the occurrence of postoperative PEP or severe PEP between the two groups. However, the combined group demonstrated significantly shorter pain relief times and hospital stays than the indomethacin group. This finding underscores the superior recovery outcomes in the combined group, highlighting the clinical significance of this approach in improving patients’ quality of life and optimizing the utilization of healthcare resources. The novelty of this study lies in its analysis of the combined effects of pancreatic duct stent placement and rectal indomethacin administration on the immune response of patients at high risk of PEP. Previous research has predominantly focused on individual treatment modalities, overlooking the potential synergistic benefits of combination therapies. Conversely, the present study demonstrated that the combined approach yields superior outcomes compared with monotherapy, offering a novel therapeutic strategy for enhancing the immune protection of patients at high risk of PEP. Furthermore, the comprehensive analysis of CD4+, CD8+, and CD4+/CD8+ provides valuable insights for clinicians, enabling more accurate assessment of patients’ immune status and facilitating informed treatment decisions.

CONCLUSION

The combination of indomethacin and pancreatic duct stent placement effectively mitigates the inflammatory response in patients at high risk for PEP following ERCP, enhances immune function, and expedites postoperative recovery, as evidenced by shorter pain relief times and hospital stays.