Efficacy of Ulinastatin in Preventing Post-ERCP Pancreatitis in High-Risk Patients: A Prospective Cohort Study

Abstract

Objective

Pancreatitis is a frequent aftermath of endoscopic retrograde cholangiopancreatography (ERCP), often associated with local and systemic complications that subsequently prolong hospitalization. Despite pharmacological and technical modalities for prophylaxis, there is still an unmet need for novel preventive measures. So, this prospective cohort study was conducted to evaluate whether ulinastatin administration prevents post-ERCP pancreatitis in high-risk scenarios.

Materials and Methods

A total of 272 patients were screened for inclusion. Finally, 172 patients were recruited. Eighty-six patients were considered to have a high risk of post-ERCP pancreatitis based on demographic and intervention-related factors. They constituted the “treatment group” and received 1 lac unit intravenous ulinastatin and standard prophylactic measures. Rest served as the “control group” and received standard care only. Incidence of pancreatitis, hyperenzymemia, pain on day 1 of the procedure, hospital expenditure, and length of hospitalization were compared.

Results

Post-ERCP pancreatitis and hyperenzymemia incidence was significantly lower in the “treatment group” (2.70% vs. 11.62%, p = 0.016; 11.63% vs. 29.07%, p = 0.004). Likewise, postprocedure pain on the visual analog scale was less in the “treatment group” (2.97 ± 0.29 vs. 3.36 ± 0.77, p < 0.001). Ulinastatin recipients had a significantly shorter hospital stay (27.57 ± 11.01 vs. 35.35 ± 21.84 hours, p = 0.007) and lesser expenditure (p = 0.039). On univariate and multivariate analysis, ulinastatin administration was associated with lower risk of post-ERCP pancreatitis: 0.181 (confidence interval [CI]: 0.038–0.852; p-value 0.031) and 0.181 (CI: 0.038–0.871; p-value 0.033), respectively.

Conclusion

Short-term ulinastatin administration was associated with reduced incidence of post-ERCP pancreatitis in high-risk patients.

 

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Keywords

hyperenzymemia - post-ERCP pancreatitis - ulinastatin

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is a widely performed endoscopic procedure for biliary and pancreatic disorders, ranging from choledocholithiasis to malignant obstructions of the biliary disorders. It contributes to the highest percentage of postprocedure complications among the mainstay endoscopic modalities. After sedation-related complications, post-ERCP pancreatitis (PEP) is the most frequent complication occurring even after a seemingly straightforward procedure. As per the literature, the incidence of PEP ranges from 2 to 11%[1] [2] with a reported mortality rate of 0.1 to 0.2%.[3] [4]

The pathogenesis of PEP remains unclear. It is thought to result from mechanical obstruction and/or hydrostatic injury, activating pancreatic enzymes and leading to local and potentially systemic inflammation.[5] Obstruction may be due to edema or trauma, most often through overmanipulation. Thus, it is crucial to recognize this and consider alternative cannulation techniques when standard attempts fail. Hydrostatic injuries can be induced by pancreatic duct (PD) injection with the use of contrast agents. Further causes for injuries include perforation of the PD side branch with a guidewire, use of electrocautery, and possibly an allergic reaction to the contrast agent.[6] With the advent of newer endoscopic techniques in cannulation, like wire-guided cannulation replacing contrast-guided ones, and the precut approach in difficult cannulations, the incidence of PEP has come down. However, there is still an unmet need for preventive pharmacological modalities. Since inception, only per-rectal nonsteroidal anti-inflammatory drugs and intravenous fluids have stood the test of time and have been endorsed by international guidelines to reduce the incidence of PEP.[7] Corticosteroids, glucagon, calcitonin, octreotide, and somatostatin failed to show efficacy in preventing PEP.[8] [9] Protease inhibitors, comprising gabexate, ulinastatin, and nafamostat, were of interest. Because of its short half-life of 55 seconds, gabexate required a continuous infusion for 13.5 hours.[10] [11] This drug never came into the limelight, considering the inconvenience of daycare procedures.

Ulinastatin, a 143 amino-acid glycoprotein, is extracted from healthy human urine and acts as a serine protease inhibitor.[12] Because of its longer half-life of 35 minutes, a single bolus dose suffices. Despite being commonly used in Japan for PEP prevention, numerous studies on the efficacy of prophylactic ulinastatin in preventing PEP have produced inconsistent results. A study by Chen et al published in 2010 found ulinastatin effective in reducing the incidence of PEP and post-ERCP hyperamylasemia (PEHA),[13] while the study by Yuhara et al published in 2014 concluded that ulinastatin was not associated with a reduced risk of PEP.[14] Since then, several additional studies on the effect of ulinastatin in preventing PEP and PEHA have been published. Due to their inconsistent results, ulinastatin is not yet recommended in the guidelines.

 

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Materials and Methods

Study Setting and Population

We conducted a prospective cohort study at a tertiary care center in Eastern India with an average volume of approximately 500 ERCPs annually ([Fig. 1]). Consecutive patients aged 18 years and above having undergone ERCP at our institute from June 1, 2022, to December 31, 2023, were screened for inclusion; patients with a history of recent onset pancreatitis, cholangitis, underlying chronic kidney disease, terminal illness, pregnancy, and posttransplant status were excluded. Normal liver function tests before intervention, women under 40, and suspicion of sphincter of Oddi dysfunction were considered high-risk factors for PEP. These patients were given intravenous ulinastatin 1 lac units in 100 mL of normal saline just before the procedure. Moreover, patients with difficult cannulation, that is, when guidewire inadvertently went in PD twice or more or the common bile duct was cannulated in five or more attempts, were also given ulinastatin postprocedure. Ulinastatin recipients were categorized as the “treatment group,” the rest constituted the “control group.” Both the groups received standard prophylactic measures, namely, per-rectal diclofenac suppository and intravenous fluids at 3 mL/kg/hr during the procedure followed by 1-L bolus over 1 hour and thereafter 3 mL/kg/hr for 6 hours. In addition, a prophylactic PD stent was placed where the double wire-guided technique was used. The study was approved by the Institutional Ethics Committee (Approval number: NHRTIICSEC/AP/037/2019).

Fig. 1 Flow diagram of the study.

 

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Follow-Up and Outcome

All patients were hospitalized for at least 12 hours after the procedure. Abdominal pain was clinically assessed the following day using the visual analog scale (VAS). Serum amylase and lipase levels were sent for all postprocedure patients. Imaging like computed tomography or ultrasonography of the abdomen was done, if required, based on clinical discretion. PEP was diagnosed based on persistent pain in the abdomen for at least 24 hours after ERCP, along with elevated serum amylase and/or lipase levels to more than three times the upper limit of regular 24-hour postprocedure.[15] Severity of pancreatitis was graded according to a modified 1991 Consensus Guidelines: mild, requiring hospitalization for 3 days or less; moderate, hospitalization for 4 to 10 days; and severe, hospitalization for more than 10 days or demanding intensive care or invasive interventions like drainage of collections.[16] Likewise, hyperenzymemia was defined as serum amylase and/or lipase levels more than three times the upper limit of normal at 24 hours after the procedure, irrespective of a diagnosis of PEP.

The incidence of PEP and hyperenzymemia was recorded for patients in either group. The duration of hospitalization and expenses incurred by them were noted.

 

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Sample Size Calculation

Sample size was calculated using the formula:

n = (Z _α/2+ Z _β)² * (p ₁(1–p ₁) + p ₂(1–p ₂)) / (p ₁–p ₂)²

where Z _α/2 is the critical value of the normal distribution at α/2 (e.g., for a confidence level of 95%, α is 0.05 and the critical value is 1.96), Z _β is the critical value of the normal distribution at β (e.g., for a power of 80%, β is 0.2 and the critical value is 0.84), and p ₁ and p ₂ are the expected sample proportions of the two groups.

In a previous study “A study on ulinastatin in preventing post-ERCP pancreatitis” by Vedamanickam et al, we have seen that proportion of pancreatitis in the ulinastatin group was 0.043 and in the placebo group was 0.173.[17] Using this formula, we needed 86 patients in each group.

 

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Statistical Analysis

IBM SPSS v29 (Chicago, Illinois, United States) was used for statistical analysis. Categorical variables were expressed in percentage (%), and continuous variables in mean ± standard deviation or median (interquartile range). Categorical variables were compared using the chi-square test. Depending on the normality of the distribution, an unpaired t-test or Mann–Whitney U test was used to compare continuous variables. The causal association was analyzed by logistic regression and expressed in terms of odds ratios (ORs).

 

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Results

During the study period, 172 patients were recruited. The treatment group comprised of 86 patients, and the rest belonged to the control group. There was no significant difference in the mean age of the study population in the treatment and control groups. The gender distribution had also been similar in these two groups. Most of the patients in either group underwent ERCP for choledocholithiasis. Malignant etiology accounted for a similar proportion of patients in either group, that is, 13.95% in the “treatment group” versus 16.28% in the “control group” (p = 0.762) ([Table 1]). Only two patients in each group, that is, 2.33%, underwent pancreatic ERCP.

Table 1 Demographic characteristics of the study population

	Total (n = 172)	Treatment group (n = 86)	Control group (n = 86)	p-Value
Age (years)[a]	49 ± 12	51 ± 12	48 ± 12	0.195
Gender[b]
Male (%)	88 (51.16%)	46 (53.49%)	42 (48.84%)	0.647
Female (%)	84 (48.84%)	40 (46.51%)	44 (51.16%)
Type of ERCP[b]
Biliary (%)	144 (97.30%)	84 (97.67%)	84 (97.67%)	0.690
Pancreatic (%)	4 (2.70%)	2 (2.33%)	2 (2.33%)
Indications:[b]
Choledocholithiasis	100 (58.14%)	51 (59.30%)	49 (56.98%)	0.762
Check cholangiogram	24 (13.95%)	12 (13.95%)	12 (13.95%)
Benign biliary stricture	15 (8.72%)	7 (8.14%)	8 (9.30%)
Malignant biliary stricture	26 (15.12%)	12 (13.95%)	14 (16.28%)
Bile duct injury	2 (1.16%)	2 (2.71%)	0
Chronic pancreatitis	2 (1.16%)	1 (1.16%)	1 (1.16%)
Pancreas divisum	2 (1.16%)	1 (1.16%)	1 (1.16%)

Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; SD, standard deviation.

^a Continuous variable expressed in mean ± SD and analyzed using unpaired t-test.

^b Categorical variable expressed in percentage (%) and analyzed using chi-square test.

Primary Outcome of Study

PEP occurred in 12 patients. Of them, 10 were in the “control group” and two in the “treatment groups” (p < 0.001; [Table 2]). Both patients in the “treatment group” had mild pancreatitis, while 2 out of 10 patients in the “control group” had moderately severe pancreatitis.

Table 2 Post-ERCP outcomes

	Total (n = 172)	Treatment (n = 86)	Control (n = 86)	p-Value
Primary outcome
Pancreatitis[a]	12 (6.98%)	2 (2.33%)	10 (11.62%)	0.016[d]
Secondary outcome
Amylase (in IU/L)[c]	175 (140–248)	150 (124–191)	190 (160–393)	< 0.001[d]
Lipase (in IU/L)[c]	92(82–118)	86 (82–95)	96 (86–378)	< 0.001[d]
Hyperenzymemia[a]	35 (20.35%)	10 (11.63%)	25 (29.07%)	0.004[d]
VAS day 1[b]	3.12 ± 0.60	2.97 ± 0.29	3.36 ± 0.77	< 0.001[d]
Hospital stay (in hours)[b]	30.42 ± 16.59	27.57 ± 11.01	35.35 ± 21.84	0.007[d]
Expenses (in rupees)[b] [d]	29953 ± 8543	29243 ± 4882	32270 ± 11537	0.039[d]

Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; IQR, interquartile range; SD, standard deviation; VAS, visual analog scale.

^a Continuous data expressed in mean ± SD and analyzed using unpaired t-test.

^b Categorical data expressed in percentage (%) and analyzed using chi-square test.

^c Continuous data expressed in median (IQR) and analyzed by Mann–Whitney U test.

^d p-Value significant.

 

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Secondary Outcome of Study

Median values of amylase and lipase were significantly higher in the “control group” (p < 0.001; [Table 2]). A substantially higher proportion of patients in the “control group” experienced hyperenzymemia, 29.07% in the “control group” compared with 11.63% in the “treatment group” (p = 0.004) ([Table 2]).

The post-ERCP hospital stay was comparatively shorter in the “treatment group” (27.57 ± 11.01 vs. 35.35 ± 21.84 hours; p = 0.007) ([Table 2]). Hospital expenditures incurred by patients in the treatment group were significantly lower (p = 0.039) ([Table 2]).

 

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Prediction of Post-ERCP Pancreatitis

On univariate and multivariate regression analysis, ulinastatin infusion periprocedurally significantly predicted a lesser incidence of PEP ([Table 3]). On multivariate and univariate analysis, OR of PEP on ulinastatin administration were 0.181 (confidence interval [CI]: 0.038–0.852; p-value 0.031) and 0.181 (CI: 0.038–0.871; p-value 0.033), respectively.

Table 3 Predictors of post-ERCP pancreatitis

	Univariate analysis			Multivariate analysis
	OR	95% CI	p-Value	OR	95% CI	p-Value
Ulinastatin administered before or after procedure	0.181	0.038–0.852	0.031[a]	0.181	0.038–0.871	0.033[a]
Age (in years)	0.978	0.936–1.023	0.331	0.981	0.933–1.032	0.462
Females	1.509	0.460–4.955	0.497	5.847	0.392–87.153	0.200
Alcohol intake	0.693	0.210–2.288	0.548	0.130	0.008–2.039	0.146
Malignant etiology	0.491	0.061–3.973	0.505	0.332	0.031–3.517	0.360

Abbreviations: CI, confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; OR, odds ratio.

Note: The values highlighted in bold illustrate that linastatin administration significantly had fewer instances of post ERCP pancreatitis. As only this co-variate yielded significant results , i.e., p-values less than 0.05, among other co-variates, the same has been highlighted in bold.

^a p-Value significant.

 

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Discussion

Our study comprised both male and female patients in nearly equal proportions (51.16 and 48.84%) with no significant difference in gender distribution across the two groups. Age distribution was also similar in the two groups (51 ± 12 vs. 48 ± 12 years). In either group, 97.67% patient underwent biliary ERCP with choledocholithiasis being the most common indication (59.30 and 56.98%). Malignant biliary strictures accounted for 13.95% in the “treatment group” and 16.28% in the “control group.” Indication wise there was no difference between the two groups.

As evident from [Table 2], incidence of not only PEP (2.33% in the treatment group vs. 11.62% in the control group; p = 0.016) but as well as incidence of hyperenzymemia (11.63% vs. 29.07%; p = 0.004) and mean VAS score on day 1 postprocedure were significantly lower in ulinastatin recipients (2.97 ± 0.29 vs. 3.36 ± 0.77; p < 0.001). Also, patients receiving ulinastatin had a shorter hospital stay (27.57 ± 11.01 vs. 35.35 ± 21.84 hours; p = 0.007) and lesser hospital expense (p = 0.039). On multivariate analysis, ulinastatin recipients had OR of 0.181 (0.038–0.871), p = 0.033.

In Vedamanickam et al's study on ulinastatin versus placebo on 46 patients, the incidence of pancreatitis and hyperamylasemia was significantly lower in the ulinastatin group (4.3% vs. 17.3%, p < 0.05).[17] Tsujino et al conducted a multicenter randomized controlled trial including 406 patients divided into 204 for ulinastatin and 202 for placebo. Ulinastatin recipients had a significantly lower incidence of hyperenzymemia (amylase, p = 0.011; lipase, p = 0.008) and a lower incidence of pancreatitis (2.9% vs. 7.4%; p = 0.041^).15 Lu et al's meta-analysis also established the efficacy of ulinastatin in preventing PEP (OR = 0.26, 95% CI: 0. 13–0.53, p = 0.0002), hyperamylasemia (OR = 0.47, 95% CI: 0.33–0.67, p < 0.001) and abdominal pain (OR = 0.56, 95% CI: 0.34–0.91, p = 0.020).[18] Another meta-analysis by Zhu et al demonstrated reduced risk of PEP (relative risk [RR] = 0.49; 95% CI: 0.33–0.74; p = 0.0006), PEHA risk (RR = 0.68; 95% CI: 0.56–0.83; p = 0.0001), and incidence of post-ERCP abdominal pain (RR = 0.67; 95% CI: 0.45–1.00; p = 0.05).[19] Fujishiro et al compared ulinastatin with gabexate in preventing PEP. One hundred and thirty-nine patients were randomly divided into three groups based on the agent and dose given: gabexate mesylate (900 mg), high-dose ulinastatin (450,000 units), and low-dose ulinastatin (150,000 units). The three groups had no significant differences in serum amylase, interleukin (IL)-6, and IL-8 levels and polymorphonuclear neutrophil elastase activity after the ERCP procedure. On multiple logistic regression analysis, endoscopic sphincterotomy was the only significant predictor for PEP and PEHA.[20]

Amidst these encouraging results, in Yoo et al's study on 216 patients, ulinastatin had been ineffective in preventing PEP in high-risk patients.[21] The beneficial roles of ulinastatin had primarily been confined to the average risk subgroup in the previously mentioned studies. However, in Yoo et al's study ulinastatin was given postprocedure in slow infusion over 5.5 hours. So, our study was conducted with ulinastatin administered selectively to patients with a high risk of PEP, where ulinastatin was given in bolus either preprocedure or just after the procedure. The pathogenesis of PEP begins just after the initial trigger with intracellular activation of trypsin. So, a bolus administration with comparatively higher plasma concentration in the initial 30 minutes might have produced better outcome in our study.[17] According to previous studies, in addition to significantly lower incidence of PEP in the ulinastatin group, there were fewer incidences of hyperenzymemia and shorter hospital stays in patients receiving ulinastatin. None of the ulinastatin recipients experienced significant adverse effects. Henceforth, ulinastatin administration considerably benefited the patients.

Intravenous fluids and per-rectal diclofenac are the only recommended preventive measures. However, intravenous fluid administration at the requisite rate may prove detrimental to patients with chronic kidney disease and cardiac comorbidities. Likewise, acute renal impairment is a contraindication to per-rectal diclofenac. In these scenarios, ulinastatin may be useful.

Our study has certain limitations. First, it is a single-center study. Second, we had limited data regarding the procedure-related risk factors for PEP, namely, cannulation time and the number of PD passes. Incorporating these data would have contributed to a more comprehensive analysis. Third, our study had limited patients. The incidence of PEP in the control group might have exceeded our expectations because of selection bias. Recruitment of more patients and randomization might have produced more generalized results. Fourth, lack of blinding might have subtly influenced the results. For instance, clinicians being aware of the protective role of ulinastatin might be less likely to interpret pain abdomen in ulinastatin recipients as pancreatitis and also it might have undermined assessment of pain, a purely subjective parameter. Henceforth, patients in the “treatment group” might have undergone less investigations and shorter hospital stay. Lastly, there was no matching or stratification. Henceforth, the study groups were heterogeneous with respect to age, gender distribution, indications, and cannulation techniques.

 

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Conclusion

Ulinastatin administration for patients at high risk of PEP was associated with reduced events of pancreatitis, shorter hospital stay, and lesser expenses. However, further multicenter studies and randomized controlled trials are required for the validation of its efficacy and clarity regarding its dosage and time of administration.

 

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Conflict of Interest

None declared.

Authors' Contributions

• S.P.: Performed ERCPs, guided the entire research work regarding the collection of data, and finalized the manuscript with modifications.

• G.B.: Writing of manuscript and statistical analysis.

• S.M.: Guided writing of manuscript and statistical analysis.

• S.P.: Collection of data and writing of the manuscript.

• S.M.: Collection of data.

• N.P.B.: Performed ERCPs.

• References

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Publication History

Article published online:
13 June 2025