Lactated Ringers With or Without Rectal Indomethacin to Prevent Post-ERCP Pancreatitis

Endoscopic retrograde cholangiopancreatography (ERCP) is commonly used diagnostic and
therapeutic intervention used in Gastroenterology. At Cooper University Hospital (CUH), we
perform approximately 700 ERCPs per year. A known complication of ERCP is post-ERCP
pancreatitis. The incidence of post-ERCP pancreatitis has been cited at anywhere from
2.6-3.5% of cases. Also, severe acute pancreatitis has been cited at rates of 0.32-0.4% and
death 0.11%.

Recent literature has cited the use of several modalities useful in preventing post-ERCP
pancreatitis. Among the modalities evaluated non-steroidal anti-inflammatory drugs (NSAIDS),
specifically rectal indomethacin, have demonstrated benefit in preventing post-ERCP. In
particular Elmunzer et al demonstrated a benefit in those with sphincter of oddi dysfunction
(SOD) and those deemed "high risk" for post-ERCP pancreatitis. Other medication such at
octretoide and corticosteroid have shown mixed results.

Additionally, recent studies have demonstrated the use of lactated ringer's solution (LR) in
lieu of normal saline (NS) in patient's with acute pancreatitis. Due to this thought process
a recent study evaluated the use of LR in preventing post-ERCP pancreatitis. The results of
this study showed that no patients who received aggressive LR hydration developed post-ERCP
pancreatitis.

As rectal indomethacin and LR infusion appear to have the most definitive evidence for
preventing post-ERCP pancreatitis, it is our hope to evaluate the combination of these two
therapies for the prevention of post-ERCP pancreatitis.

This is a double blinded, randomized prospective cohort study involving 4 treatment groups
undergoing ERCP.

All treatment arms shall receive consent, pre-procedural risk stratification, demographic
data and pre-procedural liker pain scale. All subjects shall receive a study subject number
and undergo randomization. All subjects also will receive post-procedural likert pain scale
assessment, day 1 and 30 questioning. Treatment arms shall be separated into whether subjects
are high risk or not defined in.

Time 0 (Visit 1):

Subjects undergo standard pre-procedural evaluation by nursing, anesthesia and consent for
procedure/anesthesia.

The subject shall then be evaluated for study participation and subsequently consented if
they desire to be part of the study. They may also undergo informed consent prior to the day
of their procedure during their normal office visit. All subjects must have Liver function
tests (LFTs), amylase and lipase levels drawn prior to their ERCP test. Subjects will be
excluded from study participation if they have acute pancreatitis defined as;

The diagnosis of AP is most often established by the presence of 2 of the 3 following
criteria:

(i) abdominal pain consistent with the disease (ii) serum amylase and / or lipase greater
than three times the upper limit of normal, and / or (iii) characteristic findings from
abdominal imaging

The day of their procedure, nursing shall then obtain intravenous peripheral access (standard
for ERCP). Initial demographic data and risk factor data shall be obtained. Subjects shall
then be randomized to one of the four study arms and given a study number randomly generated:

Pending which treatment arm the patient is enrolled into the subject shall then receive the
above listed therapies and undergo their procedure.

Post-procedure the interventions performed during the ERCP shall be recorded and the patient
will go through the standard recovery process. Post-procedure after recovery from anesthesia,
the patients shall then be evaluated for the presence of pain after ERCP testing on the
standard likert pain scale.

If the subject's pain has substantially increased from baseline, subjects shall then be
admitted to the hospital and LFTs, a lipase and amylase level shall be drawn and abdominal
imaging ordered if needed by the admitting physician (all the standard of care).

Time 1 Days (Visit 2 via phone):

Subjects shall be called 24 hours from ERCP to assess;

1. Presence/absence of pain

2. If pain, the severity

3. Performance of amylase and lipase

4. Whether admission, urgent care or emergency department visit did occur

Time 1-30 Days The investigator will await the subjects laboratory values and if > 3 times
the upper limit of normal contact the subject via phone.

Time 30 Days (Visit 3 via phone):

Subjects shall be contacted via phone 30 days from ERCP to assess;

1. Presence/absence of pain

2. If pain, the severity

3. Whether admission, urgent care or ED visit did occur to a healthcare facility

4. Study summary

To detect a difference of 0.24 vs 0.05 a minimum of 48 per group would be needed (using
p=0.05).

Descriptive statistics will be used to summarize demographic variables such as age, gender,
race, length of stay, as well diagnosis and disease characteristics such as reasons for ERCP,
disease intervention, pain,and outcome variables. Data tables will be generated for those
variables with means, SD, medians, IQR, and CI. The Chi-Square test will be used to determine
the main effect of treatment on ERCP induced pancreatitis. Nonparametric tests will be used
to analyze categorical data while normally distributed data will be analyzed using ANOVA to
look for treatment effect on other variables of interest.

Binary and Multinomial Logistic Regression will be used to examine predictors of outcome
within treatments and across treatments by building interactions into the model (e.g. reasons
for ERCP, intervention type). Data analysis will be performed using Systat version 13 and
SPSS version 22. A p<0.05 will be considered statistically significant.

Inclusion Criteria:

1 Subjects who are undergoing endoscopic retrograde cholangiopancreatography (ERCP)

- Age > 18 years

- Non-pregnant

- Non-prisoners

- Subjects who can sign informed consent

- Serum Creatinine < 1.2 milligrams/deciliter (mg/dL)

- Subjects without renal failure (acute or chronic)

- Subjects without congestive heart failure (ejection fraction < 40%)

- Subjects without cirrhosis of the liver

- Subjects without allergy to aspirin or non-steroidal anti-inflammatory drugs (NSAIDS)

- Subjects not on non-steroidal anti-inflammatory drugs NSAIDS prior to enrollment

Exclusion Criteria:

- Subjects who are not undergoing ERCP

- Age < 18 years

- Pregnancy

- Prisoners

- Subjects lacking the capacity to consent for themselves

- Serum Creatinine > 1.2 milligrams/deciliter (mg/dL)

- Subjects with renal failure (acute and chronic)

- Subjects with congestive heart failure (ejection fraction < 40%)

- Subjects with cirrhosis of the liver

- Subjects with allergy to aspirin or non-steroidal anti-inflammatory drugs (NSAIDS)

- Subjects with gastrointestinal hemorrhage

- Subjects on chronic non-steroidal anti-inflammatory drugs NSAIDS

- Subjects with acute pancreatitis the day of their procedure (CITE 1-3)(APPENDIX 1)