Randomized Trial of Aggressive Fluid Hydration to Prevent Post ERCP Pancreatitis
Randomized Trial of Aggressive Fluid Hydration to Prevent Post ERCP Pancreatitis
1. ERCP is a commonly performed endoscopic procedure used to treat stones and blockages of
 the bile duct as well as to manage leaks which occurs following laparoscopic gallbladder
 removal.

 2. Post ERCP pancreatitis (PEP) complicates 5-15% of biliary endoscopic procedures and
 results in considerable suffering and cost.

 3. Patients with acute pancreatitis are treated with fluids.

 4. Our aim is to assess whether prophylactic treatment with aggressive intravenous
 hydration prevents ERCP pancreatitis.

 5. In a blinded fashion patients will be randomized to aggressive intravenous versus
 moderate hydration during and aftere ERCP for standard clinical indications.

 Our hypothesis is that prophylactic treatment with aggressive intravenous hydration protects
 against 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