Randomized Trial of Aggressive Fluid Hydration to Prevent Post ERCP Pancreatitis
Condition: Pancreatitis
MeSH terms: Pancreatitis
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Aggressive Intravenous Hydration Group; Standard Fluids Arm
Intervention type(s): Other; Other
Intervention description(s): Patients in the intravenous hydration group wll be treated with lactated ringer infusion at a rate of 3cc/kg/hour during the procedure, be given a bolus of 20cc/kg immediately afterward and receive an infusion of 3cc/kg/hour for 8 hours after the procedure.; Patients randomized to the standard fluids arm will receive lactated ringers at an infusion rate of 1.5cc/kg/hour during the procedure, will receive no bolus, and will receive an infusion of lactated ringers at 1.5cc/kg for 8 hours after the procedure.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Prevention
Keywords: pancreatitis; cholangiopancreatography, endoscopic retrograde; hyperamylasemia