What literature exists supporting use of glucagon for ERCP Procedures? Are there any other procedures that have evidence supporting use as a diagnostic aid or for routine use during surgery?

Comment by InpharmD Researcher

Current literature does not highlight glucagon use in major ERCP guidelines, which instead focus on procedural techniques, though a 2022 study suggests glucagon during ERCP may reduce adverse events like pancreatitis and bleeding without significant hyperglycemia or hyperkalemia risks. Evidence supports glucagon as a diagnostic aid in procedures like abdominal vascular imaging, biopsies, and gastrostomy tube placement by reducing gastric motility, though it should be avoided in gastrojejunostomy tube placements. Additionally, intraoperative glucagon has been shown to improve the accuracy of intraoperative cholangiography (IOC), reducing false-positive rates and unnecessary ERCPs.

Background

Neither the American Society for Gastrointestinal Endoscopy (ASGE) guidelines for endoscopic retrograde cholangiopancreatography (ERCP) use in choledocholithiasis nor the European Society of Gastrointestinal Endoscopy (ESGE) guidelines for ERCP papillary cannulation and sphincterotomy techniques discuss the use of pharmacologic agents to improve the procedure success rate. The guidelines seem to focus on techniques and the different settings regarding the application of ERCP. [1], [2]

A meta-analysis of randomized controlled trials (RCTs) evaluated the effect of prophylactic glycerin trinitrate (GTN) which found it to be effective for reducing the overall incidence of post-ERCP pancreatitis and hyperamylasemia but did not reduce rates of cannulation. From 12 studies (N=2,649), the risk ratio (RR) for incidence of post-ERCP pancreatitis (PEP) was 0.67 (95% confidence interval [CI] 0.52 to 0.87). However, rates of moderate to severe PEP were not reduced (RR 0.70; 95% CI, 0.42 to 1.15). There was less incidence of hyperamylasemia with GTN treatment (RR 0.69; 95% CI 0.54 to 0.90). The cannulation success rate was not different between GTN and control (RR 1.03; 95% CI 0.99 to 1.06). Intravenous GTN may be associated with greater rates of adverse events, with some studies noting dose reduction or cessation of infusion. [3]

A previous meta-analysis also found that GTN had a lower risk of post-ERCP pancreatitis versus placebo with a reported overall pooled risk (OR) of 0.56 (95% CI 0.40 to 0.79; p=0.001). The analysis consisted of 7 randomized controlled trials (N=1,854). The sublingual form may have been more effective than the transdermal form (p=0.007 versus p=0.05); however, there was no difference between GTN and placebo regarding the overall rate of successful cannulation of bile ducts (RR 0.99; 95% CI 0.93 to 1.06). Hypotension and headache were the most reported adverse events. [4]

A review examined common miscellaneous pharmacologic agents used in interventional radiology which included bowel antiperistalsis agents among other classes (e.g., vasodilators, vasoconstrictors, antiemetics, prothrombotics). Aside from glucagon’s main utility in digital subtraction arteriography for abdominal vascular procedures, glucagon can facilitate other abdominal procedures including biopsies, abscess drainage, esophageal or colonic stenting, and gastrostomy tube placement. Glucagon decreased pyloric opening, trapping the gas in the stomach. This allowed for smooth gastrostomy tube placement for feeding. Since glucagon will hinder the ability of wire or catheter placement beyond the pylorus, its use should be avoided for gastrojejunostomy tube placement. This is as far as the review provided information on glucagon use in gastrostomy tube placement. [5]

Another review described a technique for routine percutaneous radiological gastrostomy catheter placement. Given the variations on the method used for percutaneous gastrostomy placements among radiology departments, only the key features of a routine placement were discussed. During the preparation step where the proposed puncture site is prepped, draped, and anesthetized with lignocaine, the authors noted that some institutions may use 0.5 to 1.0 mg of IV glucagon prior to gastric distension to inhibit gastric motility and emptying. [6]

References: [1] ASGE Standards of Practice Committee, Buxbaum JL, Abbas Fehmi SM, et al. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc. 2019;89(6):1075-1105.e15. doi:10.1016/j.gie.2018.10.001.
[2] Testoni PA, Mariani A, Aabakken L, et al. Papillary cannulation and sphincterotomy techniques at ERCP: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy. 2016;48(7):657-683. doi:10.1055/s-0042-108641.
[3] Ding J, Jin X, Pan Y, et al. Glyceryl trinitrate for prevention of post-ERCP pancreatitis and improve the rate of cannulation: a meta-analysis of prospective, randomized, controlled trials. PLoS One. 2013;8(10):e75645. doi:10.1371/journal.pone.0075645.
[4] Chen B, Fan T, Wang CH. A meta-analysis for the effect of prophylactic GTN on the incidence of post-ERCP pancreatitis and on the successful rate of cannulation of bile ducts. BMC Gastroenterol. 2010;10:85. doi:10.1186/1471-230X-10-85.
[5] Oppenheimer J, Ray CE Jr, Kondo KL. Miscellaneous pharmaceutical agents in interventional radiology. Semin Intervent Radiol. 2010;27(4):422-430. doi:10.1055/s-0030-1267854.
[6] Lyon SM, Pascoe DM. Percutaneous gastrostomy and gastrojejunostomy. Semin Intervent Radiol. 2004;21(3):181-189. doi:10.1055/s-2004-860876.
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What literature exists supporting use of glucagon for ERCP Procedures? Are there any other procedures that have evidence supporting use as a diagnostic aid or for routine use during surgery?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-5 for your response.


 

A Prospective, Double-Blind Trial of L-Hyoscyamine Versus Glucagon for the Inhibition of Small Intestinal Motility During ERCP

Design

Double-blinded, randomized, prospective study

N= 308

Objective

To evaluate the use of hyoscyamine sulfate versus glucagon in reducing gastrointestinal motility during diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP)

Study Groups

Glucagon (n= 153)

Hyoscyamine sulfate (n= 155)

Inclusion Criteria

Patients undergoing standard diagnostic or therapeutic ERCP

Exclusion Criteria

Patients having sphincter of Oddi manometry

Methods

Patients who could not achieve adequate visualization of the papilla for completion of the procedure were randomized (1:1) to receive either an initial dose of intravenous (IV) glucagon or hyoscyamine sulfate 0.5 mg as needed based on their baseline duodenal motility grade (0 = no motility; 1[+] = less than five contractions/minute; 2[+] = 5 to 10/minute; 3[+] = 11 to 15/minute; 4[+] = continuous). Additional doses of each agent were given in 0.2 mg increments if desired antimotility was not met 5 minutes after administration. 

Crossover to the alternative agent was allowed after a trial of four doses of the same drug. Procedure difficulty was graded on a scale from 1 to 4, with grade 1 indicating uncomplicated diagnostic or therapeutic procedure lasting less than 30 minutes to grade 4 indicating a complex therapeutic procedure lasting more than 1 hour.

Duration

Follow-up: Up to 2 hours post-procedure

Outcome Measures

Antimotility effects, adverse effects, patient acceptance, and cost

Baseline Characteristics

 

Glucagon (n= 153)

Hyoscyamine sulfate (n= 155)

p-value

Sedation per procedure 

Meperidine, mg

Midazolam, mg

 

82.8 ± 29

6.6 ± 2.6

 

80 ± 27

7 ± 5.7

-

Time to onset of effect, minutes

3.1 ± 2.3

3.5 + 2.6

Duration of effects, minutes 

14.8 ± 7.7

14.5 ± 7.8

Number of doses given, n

2.6 ± 1.9 2.3 ± 1.7

Therapeutic ERCP, n 

111 (73%)

115 (74%)

Crossover, n 

1 (0.7%)

12 (7.7%)

0.002

Predrug motility grade

0

1

2

3

4

 

0

11.2%

26.3%

49.3%

13.2%

 

0

7%

27.3%

53.8%

11.9%

Not significant

 

 

 

 

Results

Endpoint

Glucagon (n= 152)

Hyoscyamine sulfate (n= 143)

p-value 

Motility grade (no crossover)

0

1

2

3

4

 

40.8%

52%

7.2%

0

 

32.1%

51.8%

12.6%

3.5%

0

0.03

 

 

 

 

  Glucagon (n= 153)

Hyoscyamine sulfate (n= 155)

p-value

Motility grade (crossover)

0

1

2

3

4

 

40.5%

52.2%

7.2%

0

0

 

31%

50.3%

12.3%

6.5%

0

0.003

 

 

 

 

Procedure difficulty

2.41 ± 0.96

2.42 ± 0.91

Not significant

Cost per case 

$29.51

$10.45

< 0.001

Adverse Events

At one hour post-procedure: nausea, vomiting, and pain (glucagon 10.5% vs. hyoscyamine sulfate 12.6%, p= 0.58)

At two hours post-procedure: nausea, vomiting, and pain (glucagon n= 15.8% vs. hyoscyamine sulfate 25.2%, p= 0.045)

Study Author Conclusions

Currently, hyoscyamine sulfate remains a second-line agent until further data becomes available on its safety profile. In favor of using Levsin would be the associated cost advantage. Using the costs at the studied pharmacy, hyoscyamine sulfate would have cost an average of $10.45 per procedure versus $29.51 for glucagon (p < 0.001).

Furthermore, hyoscyamine sulfate is stable at room temperature and, unlike glucagon, does not require refrigeration. The study demonstrates that Levsin may be a reasonable, cost-effective alternative to glucagon as an antimotility agent during ERCP. In greater than 90% of patients, this may be the only agent required.

InpharmD Researcher Critique

This cost analysis conducted in 1997 may be outdated and not reflect current practice. The study lacks comparisons of patients' underlying medical conditions/characteristics, which may have contributing effects in study results.



References:
[1] 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(2):139-142. doi:10.1016/s0016-5107(97)70061-0.

 

Impact of Nitroglycerin and Glucagon Administration on Selective Common Bile Duct Cannulation and Prevention of Post-ERCP Pancreatitis

Design

Prospective single-center, double–blind randomized study

N= 455

Objective

To investigate the potential impact of nitroglycerin and glucagon administration on selective common bile duct (CBD) cannulation and prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis

Study Groups

Group A: sublingual nitroglycerin and glucagon (n= 227)

Group B: sterile water and hyoscine-n-butyl bromide (n= 228)

Inclusion Criteria

Intact papilla, undergoing cannulation of the CBD

Exclusion Criteria

Previous sphincterotomy, Billroth II surgery, ampullary cancer or pancreatic neoplasia infiltrating the papilla, severe hypoxemia with ventilation/perfusion imbalance, acute myocardial infarction within three months prior to study, coagulopathy (INR > 1.5), platelet count less than 50.000/mm3, procedure interruption due to severe hypotension or oxygen desaturation (post-randomization)

Methods

Patients were randomized to either group A (spray nitroglycerin 2.4 mg, 6 puffs sublingually plus 1 mg glucagon intravenously [IV]) or group B (spray sterile water, 6 puffs sublingually plus 20 mg hyoscine-n-butyl bromide IV). Sublingual nitroglycerin or sterile water was administered 1–2 minutes before starting the procedure and glucagon or hyoscine-n-butyl bromide IV was given after reaching the major papilla. 

Duration

Trial: January, 2012 to December, 2015

Follow-up: 30 days after ERCP

Outcome Measures

Primary: success rate of CBD cannulation

Secondary: post-ERCP complication rates

Baseline Characteristics

 

Group A: sublingual nitroglycerin and glucagon

(n= 227)

Group B: sterile water and hyoscine-n-butyl bromide

(n= 228)

 

Age, years

68.69 ± 15.02 65.54 ± 17.18  

Female

128 (56.4%)

124 (54.39%)  

Main indication for ERCP

Choledocholithiasis

Pancreatic cancer

Bile duct cancer

 

176 (77.53%)

16 (7.05%)

19 (8.37%)

 

180 (78.95%)

18 (7.89%)

14 (6.14%)

 

Results

Endpoint

Group A: sublingual nitroglycerin and glucagon

(n= 227)

Group B: sterile water and hyoscine-n-butyl bromide

(n= 228)

p-Value

Success rate of CBD cannulation

95.15% 82.29% < 0.001

Overall post-ERCP complication rates

24 (10.57%) 36 (15.79%) 0.101 

Post-ERCP pancreatitis

Mild

Moderate

Severe

 

7 (3.08%)

6 (2.64%)

1 (0.44%)

 

17 (7.46%)

12 (5.26%)

5 (2.19%)

0.037

Post-endoscopic sphincterotomy bleeding

Mild

Moderate

Severe

 

17 (7.49%)

15 (6.61%)

2 (0.88%)

 

19 (8.33%)

16 (7.02%)

3 (1.32%)

0.739 

Post-endoscopic sphincterotomy perforation

0 0

Adverse Events

No adverse events related to the combination regimen were observed.

Study Author Conclusions

The use of combined sublingual nitroglycerin (2.4 mg) and intravenous glucagon (1 mg) regimen facilitates CBD cannulation and reduces the rate of post-ERCP pancreatitis and the cost of the procedure. However, further comparative large-scale studies are needed to confirm our findings before definite conclusions can be drawn.

InpharmD Researcher Critique

The external validity of these results may be limited as this was a single-center study performed in a Greek hospital with all procedures performed by the same endoscopist. 



References:
[1] 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(1):50-55. doi:10.1080/00365521.2016.1228117.

 

The Safety of Glucagon use during ERCP in Diabetic Patients with Renal Insufficiency: A Case Discussion and Review of Literature

Design

Case report

Case Presentation

A 45-year-old male patient presented for an endoscopic retrograde cholangiopancreatography (ERCP) with cholangiogram to investigate a previous finding regarding a high-grade dysplasia of the cystic duct stump. The patient's medical history included type 1 diabetes, chronic kidney disease, hypertension, hyperlipidemia, and 20-pack-year smoking history. Diabetes was poorly controlled despite insulin therapy (200 to 300 mg/dL). No medication was taken on the day of surgery. After sedation and intubation, ERCP was performed to cannulate the common bile duct. Glucagon 0.25 mg IV was requested to relax the common bile duct which was repeated twice within the next 30 minutes.

However, the third dose led to tall, peaked T waves on the electrocardiogram with potassium levels risen to 6.6 mEq/L and glucose concentration of 568 mg/dL. The patient was administered calcium chloride 1,000 mg IV over 10 minutes which observed improvements in ECG. The patient also received albuterol nebulized via endotracheal tube. The procedure was completed, and the patient was extubated without complications. Postoperative potassium levels were lowered to 5.2 mEq/L.

Study Author Conclusions

This is the first report of acute hyperkalemia during ERCP. Although rare, this complication can be life-threatening if not recognized and immediately treated. In nondiabetic patients, glucagon administration causes a modest increase in plasma potassium levels, but these effects are magnified in patients with diabetes, especially in individuals who are insulin deficient or have a history of uncontrolled diabetes. The anesthesia provider should be aware of the possibility of hyperkalemia during ERCP and its effects on the myocardium. It is important to formulate a suitable approach to the management of hyperkalemia during ERCP. It may be prudent to check serum potassium and blood glucose in all patients with diabetes, especially those with chronic kidney disease.

 

 

References:
[1] Erlinger L, Monk T, McAfee S. Safety of glucagon use during endoscopic retrograde cholangiopancreatography in patients with diabetes and renal insufficiency: case discussion and review of the literature. Anesthesia eJournal. 2018;6:33-36.
Clinical safety and outcomes of glucagon use during endoscopic retrograde cholangiopancreatography (ERCP)
Design

Retrospective cohort study using a federated cloud-based network research database, TriNetX

N= 265,605

Objective To study the incidence of post-ERCP pancreatitis (PEP), ERCP-related gastrointestinal bleeding, intestinal perforation, and the need for inpatient hospitalization in patients receiving glucagon during ERCP
Study Groups

ERCP with glucagon (Group A, n= 9,008)

ERCP without glucagon (Group B, n= 256,597)

Inclusion Criteria All patients 18 years or older who underwent ERCP with glucagon use from September 1, 2010, to September 1, 2021
Exclusion Criteria Patients with postsurgical anatomy and use of enteroscopy-assisted ERCP-related data are unknown
Methods Data were collected from 92 US healthcare organizations using TriNetX. Patients were divided into two groups: those who underwent ERCP with glucagon and those without. A 1:1 propensity score matching was done based on age, gender, hypertension, diabetes mellitus, obesity, chronic kidney disease, ischemic heart disease, and chronic obstructive pulmonary disease. The primary outcomes were measured after matching
Duration Data collection from September 1, 2010, to September 1, 2021
Outcome Measures

Primary: Rates of gastrointestinal bleeding, intestinal perforation, post-ERCP pancreatitis, inpatient hospitalizations, and 30-day overall mortality

Secondary: Rates of hyperkalemia and hyperglycemia

Baseline Characteristics Characteristic ERCP + Gluc (N = 9008) ERCP no glucagon (N = 256578) P value
Age (SD) 67.72 (11.05) 68.10 (11.69) < 0.001
Female 4846 (53.80%) 140785 (54.87%) 0.04
HTN 3401 (37.76%) 70673 (27.54%) < 0.001
DM 6446 (71.56%) 162541 (63.35%) < 0.001
Obesity 2016 (22.38%) 34392 (13.40%) < 0.001
COPD 6842 (75.96%) 157115 (61.24%) < 0.001
CKD 2550 (28.31%) 48562 (18.93%) < 0.001
IHD 4057 (45.04%) 78282 (30.51%) < 0.001
CT abdomen and pelvis 2856 (31.71%) 60069 (23.41%) < 0.001
Opioid use 1923 (21.35%) 36829 (14.35%) < 0.001
Indomethacin 496 (5.51%) 10433 (4.07%) 0.10
Results Primary outcome ERCP w glucagon (Group A) N = 9008 ERCP w/o glucagon (Group B) N = 9008 RR (95 % CI)
GIB 100 (1.11) 149 (1.65) 0.67 (0.52 – 0.86)
PEP 638 (7.08) 995 (11.05) 0.64 (0.58 – 0.71)
GI Perforation 16 (0.18) 25 (0.28) 0.64 (0.34 – 1.20)
Hyperglycemia 30 (0.33) 46 (0.51) 0.65 (0.41–1.03)
Hyperkalemia 95 (1.06) 114 (1.27) 0.83 (0.64–1.09)
Hospitalization 1243 (13.80) 3676 (40.81) 0.34 (0.32 – 0.36)
Death 163 (1.81) 202 (2.24) 0.81 (0.66 – 0.99)
Adverse Events The rates of hyperkalemia and hyperglycemia did not differ between the glucagon and non-glucagon groups even after matching for diabetes, indomethacin use, obesity, and chronic kidney disease
Study Author Conclusions

Glucagon use during ERCP is associated with low rates of gastrointestinal bleeding, PEP, inpatient hospitalization, and overall mortality. After propensity matching, adverse events 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.

Critique

The study utilized a large sample size and multicentric data, which strengthens its findings. However, the retrospective design may introduce inherent biases, and the lack of data on procedure time, operator skills, and glucagon dosing limits the ability to fully understand the impact of glucagon on ERCP outcomes. Additionally, the study did not account for the severity of PEP or the use of pancreatic duct stenting, which could confound the results. Future prospective studies are needed to address these limitations and provide more definitive conclusions.

 

References:
[1] Perisetti A, Goyal H, Sharma N. Clinical safety and outcomes of glucagon use during endoscopic retrograde cholangiopancreatography (ERCP). Endosc Int Open. 2022;10(4):E558-E561. Published 2022 Apr 14. doi:10.1055/a-1747-3242
The Impact of Intraoperative Glucagon on the Diagnostic Accuracy of Intraoperative Cholangiogram for the Diagnosis of Choledocholithiasis: Experience from a Large Tertiary Care Center
Design

Retrospective study at a tertiary care center

N= 1455

Objective To understand the change in diagnostic accuracy of intraoperative cholangiogram (IOC) to detect choledocholithiasis with intraoperative glucagon
Study Groups

Patients who received intraoperative glucagon (n= 374)

Patients who did not receive intraoperative glucagon (n= 1081)

Inclusion Criteria Adult patients who underwent laparoscopic cholecystectomy with IOC from February 2013 to December 2021
Exclusion Criteria Not specified
Methods Patients underwent laparoscopic cholecystectomy with IOC. Intraoperative glucagon was administered at the discretion of the surgeon, with a standard dose of 1 mg intravenously. A repeat IOC was performed within 5 minutes of glucagon administration. Diagnostic accuracy was assessed by comparing IOC findings with post-operative ERCP results
Duration February 2013 to December 2021
Outcome Measures Diagnostic accuracy of IOC
Baseline Characteristics Characteristic All patients (n= 1455)
Age, years, median (IQR) 38 (29–49)
BMI, median (IQR) 30 (26–36)
Sex - Female 1235 (84.8%)
Race - Hispanic 1333 (91.6%)
Symptoms on admission - Abdominal pain 1450 (99.6%)
Cholecystitis 796 (54.7%)
Results Endpoint Pre-Glucagon Administration Post-Glucagon Administration
Sensitivity (95% CI) 88.3 (85.16% to 91.05%) 86.9 (83.60% to 89.77%)
Specificity (95% CI) 78 (75.33% to 80.68%) 83 (80.48% to 85.35%)
Positive predictive value (95% CI) 67.3 (64.61% to 70.06%) 72.4 (69.42% to 75.19%)
Negative predictive value (95% CI) 92.8 (91.08% to 94.36%) 92.5 (90.77% to 93.97%)
Diagnostic Accuracy (95% CI) 81.5 (79.47% to 83.54%) 84.3 (82.36% to 86.18%)
Adverse Events Not specified
Study Author Conclusions Intraoperative glucagon administration enhances the diagnostic accuracy of IOC by improving specificity and positive predictive value, thereby reducing false-positive rates and unnecessary ERCPs.
Critique The study's retrospective design may introduce biases and confounders. The large sample size is a strength, but the lack of detailed adverse event reporting and exclusion criteria are limitations. Further randomized controlled trials are needed to validate findings and assess cost-effectiveness.

 

References:
[1] Mittal N, Ali FS, Machado AP, et al. The Impact of Intraoperative Glucagon on the Diagnostic Accuracy of Intraoperative Cholangiogram for the Diagnosis of Choledocholithiasis: Experience from a Large Tertiary Care Center. Diagnostics (Basel). 2024;14(13):1405. Published 2024 Jul 1. doi:10.3390/diagnostics14131405