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.
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).
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]).
Table 1
Baseline characteristics and clinical outcomes in patients who has ERCP with glucagon
compared to individuals ERCP without glucagon
|
Before matching
|
After matching[1]
|
|
Characteristic
|
ERCP + Gluc
N = 9008
Mean (SD) or n (%)
|
ERCP no glucagon
N = 256578
Mean (SD) or n (%)
|
P value
|
ERCP + Gluc
N = 9008
Mean (SD) or n (%)
|
ERCP no glucagon
N = 9008
Mean (SD) or n (%)
|
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.
Table 2
Clinical outcomes in the subgroup analysis based on patients with ERCP and glucagon
(Group 1) to ERCP without glucagon (Group 2) after propensity matching.
|
Before matching
|
After matching
|
|
Primary outcome
|
ERCP w glucagon (Group A)
N = 9008
|
ERCP w/o glucagon (Group B)
N = 256578
|
RR (95 % CI)
|
ERCP w glucagon (Group A)
N = 9008
|
ERCP wo glucagon (Group B)
N = 9008
|
RR (95 % CI)
|
|
GIB
|
100 (1.11)
|
3420 (1.33)
|
0.83 (0.68 – 1.01)
|
100 (1.11)
|
149 (1.65)
|
0.67 (0.52 – 0.86)
|
|
PEP
|
638 (7.08)
|
27725 (10.81)
|
0.66 (0.61 – 0.71)
|
638 (7.08)
|
995 (11.05)
|
0.64 (0.58 – 0.71)
|
|
GI Perforation
|
16 (0.18)
|
627 (0.24)
|
0.73 (0.44 – 1.19)
|
16 (0.18)
|
25 (0.28)
|
0.64 (0.34 – 1.20)
|
|
Hyperglycemia
|
30 (0.33)
|
1,415 (0.55)
|
0.60 (0.42–0.87)
|
30 (0.33)
|
46 (0.51)
|
0.65 (0.41–1.03)
|
|
Hyperkalemia
|
95 (1.55)
|
2017 (0.79)
|
1.34 (1.09–1.64)
|
95 (1.06)
|
114 (1.27)
|
0.83 (0.64–1.09)
|
|
Hospitalization
|
1243 (13.80)
|
104237 (40.63)
|
0.34 (0.32 – 0.36)
|
1243 (13.80)
|
3676 (40.81)
|
0.34 (0.32 – 0.36)
|
|
Death
|
163 (1.81)
|
4904 (1.91)
|
0.95 (0.81 – 1.11)
|
163 (1.81)
|
202 (2.24)
|
0.81 (0.66 – 0.99)
|
ERCP, endoscopic retrograde cholangiopancreatography; CI, confidence interval; RR,
risk ratio; GIB, gastrointestinal bleeding; PEP, post-ERCP pancreatitis.
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.
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.
