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DOI: 10.1055/a-1747-3242
Clinical safety and outcomes of glucagon use during endoscopic retrograde cholangiopancreatography (ERCP)
Abstract
Background and study aims Injectable glucagon enables easier biliary cannulation by inhibiting gastrointestinal motility and decreasing the frequency and amplitude of phasic activity of the sphincter of Oddi during endoscopic retrograde cholangiopancreatography (ERCP). Data about the safety profile of glucagon use and patient clinical outcomes are scarce.
Patients and methods We used a federated cloud-based network research database, TriNetX, comprising 92 US healthcare organizations to find adult patients undergoing ERCP with glucagon use (Group A) vs. without using glucagon (Group B) from August 1, 2010, to August 1, 2021. The primary outcomes were rates of gastrointestinal bleeding, gastrointestinal perforation, post-ERCP pancreatitis, inpatient hospitalizations, and 30-day overall mortality measured after 1:1 propensity matching of the groups based on the baseline demographics and comorbidities.
Results There were 9,008 patients in Group A compared to 256,597 in Group B. After matching, Group A patients had lower rates of gastrointestinal bleeding (risk ratio [RR], 0.68; CI, 0.52–0.86), post-ERCP pancreatitis (RR, 0.64; CI, 0.58–71), inpatient hospitalization (RR 0.34; CI:0.32 to 0.36) and overall mortality (RR, 0.81; CI, 0.66–0.99). The rates of gastrointestinal perforation (RR, 0.64; CI: 0.34 to 1.19), hyperkalemia (RR, 0.83; CI, 0.64–1.09) and hyperglycemia (RR, 0.65; CI, 0.41–1.03) did not differ between the two groups.
Discussion Glucagon use during ERCP was associated with low rates of gastrointestinal bleeding, post-ERCP pancreatitis, inpatient hospitalization, and overall mortality. Moreover, the rates of hyperkalemia and hyperglycemia did not differ between the two groups even after matching for diabetes, indomethacin use, obesity, and chronic kidney disease.
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Introduction
Endoscopic retrograde cholangiopancreatography (ERCP) is one of the most commonly performed hepatobiliary and pancreatic duct interventions. Increased duodenal motility could interfere with selective biliary cannulation (SBC), increasing the risk of post-ERCP pancreatitis (PEP). In most cases, motility is overcome by air insufflation and the short and stable position of the duodenoscope. However, in some cases, even these attempts fail, requiring use of antimotility agents [1]. Multiple duodenal antimotility agents such as hyoscyamine sulfate, atropine, octreotide, and glucagon have been used in the past [2]. Among these, glucagon has been used widely during ERCP to achieve this purpose [3]. However, its action is short-lived and multiple doses might be required to reduce the duodenal motility. Furthermore, it can cause electrolyte imbalances such as hyperkalemia and hyperglycemia. Large-scale studies to assess the safety profile and clinical outcomes in patients receiving glucagon during ERCP are non-existent. Hence, we aim to study the incidence of PEP, ERCP-related gastrointestinal bleeding, intestinal perforation, and the need for inpatient hospitalization in patients receiving glucagon during ERCP.
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Patients and methods
We used TriNetX (a federated cloud-based network research database) comprising multiple US healthcare organizations (HCOs). A total of 92 HCOs were included for the data extraction. All patients 18 years or older who underwent ERCP with glucagon use were included in Group A (glucagon group). Similarly, patients who underwent ERCP without glucagon use were classified as Group 2 (non-glucagon group). The data weree collected from September 1, 2010, to September 1, 2021, over a period of 11 years. The primary outcomes were gastrointestinal bleeding rates, intestinal perforation, PEP, inpatient hospitalizations and 30-day overall mortality. gastrointestinal bleeding was defined as any episodes of hematemesis or melena after the ERCP. PEP was defined based on the revised Atlanta criteria [4]. The clinical outcomes were measured after 1:1 propensity matching of the groups based on the baseline demographics and comorbidities (see supplementary section). A 1:1 propensity score matching was done based on the following variables: patients’ age, gender, hypertension (HTN), diabetes mellitus (DM), obesity, chronic kidney disease (CKD), ischemic heart disease (IHD), and chronic obstructive pulmonary disease (COPD).
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Results
A total of 9,008 patients were included in the glucagon group (Group A). They were compared with 256,597 patients in non-glucagon group (control, Group B). Demographics, comorbidities of the patients, use of imaging and medications are noted in [Table 1]. Male to female ratio was 45.1 % vs. 54.9 %. Patients in the glucagon group had higher rates of receiving indomethacin but it was not statistically significant (583 [6.5 %] vs. 496 [5.5 %]; P = 0.086). After matching, group 1 (glucagon group) patients had lower rates of gastrointestinal bleeding (risk ratio [RR], 0.68; CI, 0.52–0.86), PEP (RR, 0.64; CI, 0.58–0.71), inpatient hospitalization (RR, 0.34; CI, 0.32–0.36) and overall mortality (RR, 0.81; CI, 0.66–0.99). The rates of gastrointestinal perforation (RR, 0.64; CI, 0.34–1.19), hyperkalemia (RR, 0.83; CI, 0.64–1.09) and hyperglycemia (RR, 0.65; CI, 0.41–1.03) did not differ between the two groups ([Table 2]).
Before matching |
After matching[1] |
|||||
Characteristic |
ERCP + Gluc |
ERCP no glucagon |
P value |
ERCP + Gluc |
ERCP no glucagon |
P value |
Demographics |
||||||
Age (SD) |
67.72 (11.05) |
68.10 (11.69) |
< 0.001 |
67.72 (11.05) |
67.79 (11.02) |
0.67 |
Female |
4846 (53.80) |
140785 (54.87) |
0.04 |
4846 (53.80) |
4811 (53.41) |
0.60 |
Comorbidities |
||||||
HTN |
3401 (37.76) |
70673 (27.54) |
< 0.001 |
3401 (37.76) |
3112 (34.55) |
< 0.001 |
DM |
6446 (71.56) |
162541 (63.35) |
< 0.001 |
6446 (71.56) |
6439 (71.48) |
0.91 |
Obesity |
2016 (22.38) |
34392 (13.40) |
< 0.001 |
2016 (22.38) |
1632 (18.12) |
< 0.001 |
COPD |
6842 (75.96) |
157115 (61.24) |
< 0.001 |
6842 (75.96) |
6864 (76.20) |
0.71 |
CKD |
2550 (28.31) |
48562 (18.93) |
< 0.001 |
2550 (28.31) |
2569 (28.52) |
0.75 |
IHD |
4057 (45.04) |
78282 (30.51) |
< 0.001 |
4057 (45.04) |
4032 (44.76) |
0.71 |
Radiology |
||||||
CT abdomen and pelvis |
2856 (31.71) |
60069 (23.41) |
< 0.001 |
2856 (31.71) |
2833 (31.45) |
0.71 |
Medications |
||||||
Opioid use |
1923 (21.35) |
36829 (14.35) |
< 0.001 |
1923 (21.35) |
1927 (21.39) |
0.94 |
indomethacin |
496 (5.51) |
10433 (4.07) |
0.10 |
496 (5.51) |
583 (6.47) |
0.09 |
ERCP, endoscopic retrograde cholangiopancreatography; SD, standard deviation; HTN, hypertension; DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; ID, ischemic heart disease.
1 A 1:1 propensity score matching was done based on the following variables: age, gender, HTN, DM, obesity, CKD, IHD, and COPD.
ERCP, endoscopic retrograde cholangiopancreatography; CI, confidence interval; RR, risk ratio; GIB, gastrointestinal bleeding; PEP, post-ERCP pancreatitis.
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Discussion
ERCP remains the most commonly used therapeutic intervention for accessing hepatobiliary and pancreatic ducts [5]. Adequate visualization of the ampulla and duodenoscope stability is essential for SBC. Glucagon is the most commonly used medication among all pharmacological agents to decrease duodenal motility.
This study found that glucagon use during ERCP was associated with reduced risk of PEP, post-procedure gastrointestinal bleeding, inpatient hospitalization, and overall mortality. Furthermore, adverse events (AEs) such as development of hyperglycemia, hyperkalemia, and intestinal perforation did not differ between the glucagon and no-glucagon groups.
Glucagon inhibits gastrointestinal motility by relaxation of smooth muscles. It also has sphincter-relaxing properties, enabling SBC [6]. However, its effect is short-lived due to its short half-life, and multiple doses might be needed to achieve its intended effects. ERCP is associated with multiple AEs such as gastrointestinal bleeding, intestinal perforation, and PEP requiring inpatient hospitalization [7]. gastrointestinal bleeding during ERCP could be due to post-sphincterotomy and non-sphincterotomy causes such as duodenoscope-associated trauma to the duodenum, aggressive suction, especially in patients with underlying coagulopathy [8]. Impaired visualization can worsen these effects due to accidental mucosal injury, especially during endoscopic biliary sphincterotomy [9]. Decreasing duodenal motility and stabilization of ampulla could reduce the risk of these adverse events [10]. In our study, the risk of gastrointestinal bleeding after ERCP among glucagon users was reduced by 34 % (RR, 0.68; CI, 0.52–0.86). Although this effect could be related to reduced motility by glucagon, the precise mechanisms involved remain to be studied. In addition to nausea and vomiting, reports of biochemical abnormalities such as hyperkalemia and hyperglycemia have been reported with glucagon [11]. Therefore, it remains unclear if the use of glucagon during ERCP can affect its outcomes.
PEP is the most common complication of ERCP, which could be related to patient and procedural factors. Difficult cannulation, papillary trauma by repetitive cannulation, pancreatic sphincterotomy, and contrast injection-induced acinarization of the pancreas contribute to PEP [7]. Most of these complications could be reduced by proper visualization, subtle and skilled movements of the duodenoscope by a skilled endoscopist [12]. Past studies have shown that combined use of sublingual nitroglycerin and IV glucagon has shown to be associated with decreased PEP risk [13]. In our study, the incidence of PEP was significantly lower in the glucagon group (RR, 0.64; CI, 0.58– 0.71). Another significant finding of our study is lower post-procedure hospitalizations and overall mortality rates in the glucagon group.
We acknowledge some limitations with our study. First, risk stratification of patients who were at a higher risk of PEP and other AEs could not be performed due to the unavailability of the relevant information in the database. A number of patient and proceduralist factors, such as procedure time, operator skills, and pancreatic duct cannulation, can affect the PEP occurrence. These factors could potentially confound the results of the study. Post-ERCP gastrointestinal bleeding could be related to esophageal, gastric, and duodenal injury, including sphincter trauma. Use of antithrombotic agents can potentiate the effects the gastrointestinal bleeding. Although glucagon can reduce gastrointestinal peristalsis and improve visualization, other factors such as time spent during the ERCP procedure, sphincterotomy and hydration status can confound these results.
It is possible that patients with difficult SBC received glucagon and might have additional measures to reduce PEP (pancreatic duct stenting, use of indomethacin, and aggressive hydration). However, we did not find statistically significant higher use of indomethacin among patients receiving glucagon. Information about PEP severity, pancreatic duct stenting, procedure time, and number of cannulation attempts was not available. In addition, the information about the total glucagon dose used in each procedure was not available. Also, the information about trainee involvement and skillset and experience of endoscopists was not present in the database. We excluded patients with postsurgical anatomy and use of enteroscopy-assisted ERCP-related data are unknown. Studies correlating direct evidence of papillary sphincter relaxation and SBC are missing; this is likely dependent of patient, procedure- and operator-dependent factors. Performing studies keeping these variables constant and evaluating correlation between the dose of glucagon and SBC might offer further insights. Finally, retrospective studies are subjected to inherent bias, which could affect the interpretation of this study. Nevertheless, a large sample size with the use of multicentric data could potentially overcome some of these limitations.
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Conclusions
Glucagon use during ERCP is associated with low rates of gastrointestinal bleeding, PEP, inpatient hospitalization, and overall mortality. In addition, after propensity matching, AEs related to glucagon use, such as the rates of hyperkalemia and hyperglycemia, did not differ between the glucagon users and non-users. Future prospective large-scale studies are needed to assess the dosing and administration patterns of glucagon that are necessary to achieve these advantages.
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Competing interests
Abhilash Perisetti: None. Hemant Goyal: Consultant – Aimloxy. Neil Sharma: Consultant – Boston scientific, MedTronic, STERIS, Mauna Kea , Medical advisory board – endoscopynow, MedTronic, STERIS, Mauna Kea
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References
- 1 Bosley ME, Zamora IJ, Neff LP. Choledocholithiasis-a new clinical pathway. Transl Gastroenterol Hepatol 2021; 6: 35
- 2 Lahoti S, Catalano MF, Geenen JE. et al. A prospective, double-blind trial of L-hyoscyamine versus glucagon for the inhibition of small intestinal motility during ERCP. Gastrointest Endosc 1997; 46: 139-142
- 3 Katsinelos P, Lazaraki G, Chatzimavroudis G. et al. Impact of nitroglycerin and glucagon administration on selective common bile duct cannulation and prevention of post-ERCP pancreatitis. Scand J Gastroenterol 2017; 52: 50-55
- 4 Mederos MA, Reber HA, Girgis MD. Acute pancreatitis: a review. JAMA 2021; 325: 382-390
- 5 McCune WS, Shorb PE, Moscovitz H. Endoscopic cannulation of the ampulla of vater: a preliminary report. Ann Surg 1968; 167: 752-756
- 6 Carr-Locke DL, Gregg JA, Aoki TT. Effects of exogenous glucagon on pancreatic and biliary ductal and sphincteric pressures in man demonstrated by endoscopic manometry and correlation with plasma glucagon. Dig Dis Sci 1983; 28: 312-320
- 7 Johnson KD, Perisetti A, Tharian B. et al. Endoscopic retrograde cholangiopancreatography-related complications and their management strategies: a “scoping” literature review. Dig Dis Sci 2020; 65: 361-375
- 8 Forbes N, Leontiadis GI, Vaska M. et al. Adverse events associated with endoscopic retrograde cholangiopancreatography: protocol for a systematic review and meta-analysis. BMJ Open 2021; 11: e053302
- 9 Köksal AŞ, Eminler AT, Parlak E. Biliary endoscopic sphincterotomy: Techniques and complications. World J Clin Cases 2018; 6: 1073-1086
- 10 Kim J. Training in endoscopy: endoscopic retrograde cholangiopancreatography. Clin Endosc 2017; 50: 334-339
- 11 Williams ME. Hyperkalemia. Critical Care Clinics 1991; 7: 155-174
- 12 Kahaleh M, Freeman M. Prevention and management of post-endoscopic retrograde cholangiopancreatography complications. Clin Endosc 2012; 45: 305-312
- 13 Pekgöz M. Post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review for prevention and treatment. World J Gastroenterol 2019; 25: 4019-4042
Corresponding author
Publication History
Received: 10 October 2021
Accepted after revision: 14 December 2021
Article published online:
14 April 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References
- 1 Bosley ME, Zamora IJ, Neff LP. Choledocholithiasis-a new clinical pathway. Transl Gastroenterol Hepatol 2021; 6: 35
- 2 Lahoti S, Catalano MF, Geenen JE. et al. A prospective, double-blind trial of L-hyoscyamine versus glucagon for the inhibition of small intestinal motility during ERCP. Gastrointest Endosc 1997; 46: 139-142
- 3 Katsinelos P, Lazaraki G, Chatzimavroudis G. et al. Impact of nitroglycerin and glucagon administration on selective common bile duct cannulation and prevention of post-ERCP pancreatitis. Scand J Gastroenterol 2017; 52: 50-55
- 4 Mederos MA, Reber HA, Girgis MD. Acute pancreatitis: a review. JAMA 2021; 325: 382-390
- 5 McCune WS, Shorb PE, Moscovitz H. Endoscopic cannulation of the ampulla of vater: a preliminary report. Ann Surg 1968; 167: 752-756
- 6 Carr-Locke DL, Gregg JA, Aoki TT. Effects of exogenous glucagon on pancreatic and biliary ductal and sphincteric pressures in man demonstrated by endoscopic manometry and correlation with plasma glucagon. Dig Dis Sci 1983; 28: 312-320
- 7 Johnson KD, Perisetti A, Tharian B. et al. Endoscopic retrograde cholangiopancreatography-related complications and their management strategies: a “scoping” literature review. Dig Dis Sci 2020; 65: 361-375
- 8 Forbes N, Leontiadis GI, Vaska M. et al. Adverse events associated with endoscopic retrograde cholangiopancreatography: protocol for a systematic review and meta-analysis. BMJ Open 2021; 11: e053302
- 9 Köksal AŞ, Eminler AT, Parlak E. Biliary endoscopic sphincterotomy: Techniques and complications. World J Clin Cases 2018; 6: 1073-1086
- 10 Kim J. Training in endoscopy: endoscopic retrograde cholangiopancreatography. Clin Endosc 2017; 50: 334-339
- 11 Williams ME. Hyperkalemia. Critical Care Clinics 1991; 7: 155-174
- 12 Kahaleh M, Freeman M. Prevention and management of post-endoscopic retrograde cholangiopancreatography complications. Clin Endosc 2012; 45: 305-312
- 13 Pekgöz M. Post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review for prevention and treatment. World J Gastroenterol 2019; 25: 4019-4042