Randomized Trial of Aggressive Fluid Hydration to Prevent Post ERCP Pancreatitis

1.0 BACKGROUND AND HYPOTHESES

Post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is defined as the
development of epigastric pain radiating to the back accompanied by either an increase in
the pancreatic enzymes (amylase and lipase) to greater than three times the upper limit of
normal or cross sectional imaging showing inflammation of the gland. Based on length of
hospitalization it is categorized as mild (2-3 days), moderate (4-10 days), or severe (>10
days). Cases complicated by hemorrhage, pseudocyst, phlegmon formation or requiring
percutaneous intervention or surgery are also scored as severe.

Post ERCP pancreatitis is the leading complication of biliary endoscopic procedures and
could potentially lead to considerable morbidity. The overall incidence of ERCP
pancreatitis ranges from 5% in the community to 15% in centers where advanced ERCP including
pancreatic interventions are performed.

Proposed mechanisms include protease and free radical mediated inflammation, abnormal
sphincter of oddi pressure, and elevated pancreatic exocrine activity. Measures to prevent
post-ERCP pancreatitis aim to curb these processes.

Numerous trials studying the use of various preventive therapies including octreotide and
protease inhibitors have been for the most part disappointing. There have been more than
twenty clinical trials examining the efficacy of somatostatin and octreotide which inhibit
pancreatic exocrine stimulation. A meta-analysis of nine high quality trials of somatostatin
showed that overall the medication did not reduce post ERCP pancreatitis. Gabexylate
mesylate and ulnistatin which inhibit pancreatic proteases have also shown to not
significantly reduce post ERCP pancreatitis. Numerous studies have also shown that
corticosteroids do not diminish the likelihood of post-ERCP pancreatitis.

The mainstay of treatment for acute pancreatitis independent of origin is aggressive
hydration. The rationale for this is that hypovolemia and microvascular hypoperfusion are
critical to the development of pancreatic necrosis. In animal models it has been
demonstrated that pancreatic blood flow decreases in the setting of pancreatitis. Regions of
hypoperfusion correlate with regions of severe histologic inflammation.

Studies of fluid resuscitation in patients with interstitial pancreatitis have demonstrated
that those treated with inadequate fluid resuscitation have an increased risk of developing
pancreatic necrosis.

Several high profile studies have demonstrated that aggressive early fluid resuscitation on
the order of 3.4-4.6 liters in the first 24 hours, particularly using lactated ringers is
associated with significantly reduced mortality.

In a well done retrospective study Reddy et al demonstrated that patients at high risk for
post ERCP pancreatitis (and those with early signs) managed with an aggressive fluid
resuscitation protocol (defined as D5 ½ NS at 200cc/hour IV) had a significantly improved
clinical course compared to those who were not managed according to the protocol.12 Among
those high risk patients who were managed according to protocol only 12.5% developed
moderate or severe pancreatitis, compared to 61.6% who were not managed according to the
protocol. The respective median lengths of hospitalization were 3 days compared to 7 days.

In the proposed study our intervention is to prophylactically treat a random group of
patients undergoing ERCP with the standard therapy for post ERCP pancreatitis, fluids, in an
effort to prevent its development. As a safeguard at 2 hours after the procedure (when the
anesthesia from the procedure has typically cleared) any patient who has evidence of
pancreatitis is crossed over into the treatment arm. The major potential adverse outcome
which could be associated with the therapy is clinical fluid overload as manifested as chest
pain, dyspnea or hypoxia as well as pleural effusion, peripheral edema, ascites, anasarca,
or pulmonary edema. We will assess the patients for these potential complications and treat
them accordingly.

The goal for this pilot study is to analyze the efficacy of aggressive hydration in
preventing post ERCP pancreatitis. Our hope is to stimulate interest in this topic and
clarify if it could possibly lead to a large-scale study in the near future.

2.0 OBJECTIVES AND PURPOSE The primary treatment for pancreatitis regardless of the etiology
is aggressive fluid resuscitation. Our long-standing aim is to determine whether aggressive
intravenous hydration during and immediately after ERCP decreases the incidence of post ERCP
pancreatitis. The aim of the current study is to determine how large the effect will be to
appropriately power a larger randomized trial.

3.0 STUDY DESIGN

The study will be a prospective single blind randomized controlled trial consisting of 60
patients who will undergo ERCP at the LAC+USC Medical Center for standard indications.
Patients will be randomly assigned using a computer generated randomization schedule, 40
will be allocated to the treatment (aggressive intravenous hydration) and 20 will be
allocated to standard care. This will allow us to examine whether the rate of pancreatitis
under usual care is similar to published rates (about 15%), and also allow us greater
ability to detect decreases in that rate attributable to the treatment in our small pilot
sample. We defined aggressive intravenous hydration as lactated ringers (LR) IV at 3 mL kg-1
hr-1 during the procedure, with 20cc/kg LR IV bolus immediately afterward, and LR IV at 3 mL
kg-1 hr-1 x 8 hours. Those in the control arm will receive standard fluids which we define
as LR at 1.5 mL kg-1 hr-1 and for 8 hours afterwards

Once the patients begin receiving the fluids, volume status will be monitored to assess for
any signs of fluid overload or deficits that will require an adjustment to the fluid
resuscitation rates. Imbalances in volume status will be monitored clinically by assessing
for tachycardia, orthostatic hypotension based on blood pressure measurements, pulmonary and
peripheral edema. Based on the hydration status, adjustments will be made accordingly to
the fluid resuscitation rates to correct the underlying problem.

Numerous studies have attempted to investigate the best test available to assess for
post-ERCP pancreatitis, since solely relying on clinical presentation is unreliable.
Amylase levels have emerged as a reliable indicator of post-ERCP pancreatitis as lipase
usually rises later in pancreatitis and as a result may not be as useful in the early
prediction of post-ERCP pancreatitis.13 In our study, the patients will be assessed at 2
hours and 8 hours after the procedure for epigastric pain and an amylase will be sent.
Epigastric pain will be assessed using a Likert scale in which 10 is the most severe pain, 0
is no pain, and a value of greater than 3 signifies moderate or greater pain. A cutoff
greater than 3 is used in an effort not to include patients with mild transient discomfort
due to retained air after endoscopy.

The primary outcome measure for post ERCP pancreatitis will be based on if the patients have
significant epigastric pain and amylase greater than three times the upper limit of normal.
Those in the control group who develop pancreatitis will be given a 20cc/kg LR IV bolus and
treated with LR at 3cc/kg/hour. Patients who develop pancreatitis will be fasted and
otherwise the patients will be started on clears and subsequently their diet will be
advanced as tolerated.

Patients who develop pancreatitis will be followed twice daily until discharge in order to
define whether the episodes were mild (2-3 days hospitalization), moderate (4-10 days of
hospitalization), or severe (>10 days hospitalization or complications including hemorrhagic
pancreatitis, pseudocyst, phlegmon, or requiring percutaneous or surgical procedure).

4.0 SELECTION AND WITHDRAWAL OF SUBJECTS

SEE ELIGIBILIBILITY SECTION

5.0 STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY MANAGEMENT PLAN

1. Men and women will be stratified by sex and the following randomization and treatment
algorithm performed during and after the ERCP procedure.

2. The treatments are as shown

Randomization Fluids Mode of Introduction Rate during procedure Post procedure Bolus Post
procedure rate Time of treatment post procedure (hours) Aggressive Hydration Lactated
Ringer (LR) Intravenous (IV) 3cc/kg 20cc/kg 3cc/kg 8 Standard Hydration LR IV 1.5cc/kg None
1.5cc/kg 8

.

6.0 ASSESSMENT OF EFFICACY AND SAFETY

The major adverse outcome which could be associated with the therapy is clinical fluid
overload. Patients will be interviewed and examined for symptoms and signs that may suggest
this adverse reaction including chest pain, dyspnea or hypoxia as well as pleural effusion,
peripheral edema, ascites, anasarca, or pulmonary edema.

All adverse events will be reported to the principal investigator. These include event which
occur during the initial 24 hour of the procedure and at any time afterward. The entire
study team will meet to report adverse events on a biweekly basis. Reports of fluid overload
will be submitted to the IRB. Adverse events which occur during the trial will also be
reviewed with another faculty physician in the Gastroenterology Division.

7.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS

SEE ENDPOINTS SECTION

8.0 STATISTICAL CONSIDERATIONS

We are performing a single blind randomized study of aggressive versus standard fluids to
prevent post ERCP pancreatitis. While our long term goal is to assess whether
prophylactically treating patients undergoing ERCP with aggressive hydration will decrease
the incidence of post ERCP pancreatitis our current goal is to assess whether the study is
feasible and to assess how large the effect will be. Patients allocated to standard care
will be used to test this rate in our sample population.

The primary outcome of pancreatitis development within 8 hours of ERCP will be tested using
Fisher's exact chi-squared to compare the rate of pancreatitis between groups. Results from
this test will allow for estimation of sample size for a fully powered clinical trial. This
same method will be used to test the secondary aim of when pancreatitis was first detected
(2 hours vs 8 hours), though given the small number of participants who will likely develop
pancreatitis (< 15%) the primary aim of this comparison is to inform on monitoring and
safety for a fully powered trial. To test the secondary outcome of pain, a repeated measures
ANOVA will be used to compare pain ratings between groups at 2 and 8 hours. Because this is
a pilot study, the primary aim is to detect effect sizes and clinical relevance of
outcomes.. Statistical analyses will be performed by biostatisticians at the Biostatistical
and Bioinformatics Resource Group within the SC CTSI.

Inclusion Criteria:

- All Inpatients aged 18 to 70 years undergoing ERCP for the first time

- Patients undergoing ERCP for standard clinical indications

Exclusion Criteria:

- Ongoing acute pancreatitis

- Ongoing hypotension including those with sepsis

- Cardiac insufficiency (CI, >NYHA Class II heart failure)

- Renal insufficiency (RI, creatinine clearance <40mL/min)

- Severe liver dysfunction (albumin < 3mg/dL)

- Respiratory insufficiency (defined as oxygen saturation < 90%)

- Greater than 70 years of age

- Pregnancy

- Hyponatremia (Na+ levels < 135mEq/L))

- Hypernatremia (Na+ levels > 150mEq/L) will be excluded.

- Edema or anasarca

- Ascites