A Randomized Controlled Pilot Trial of Indomethacin in Acute Pancreatitis

Background:

AP is an inflammatory disease with a highly variable clinical course that is potentially
lethal. This disease is currently the leading cause of gastrointestinal-related hospital
admissions in the United States and continues to rise in incidence. The inciting event
leading to the development of AP is the premature activation of the digestive pro-enzyme
trypsinogen to trypsin within pancreatic acinar cells, resulting in pancreatic auto-digestion
and inflammation. Inflammation localized to the gland can subsequently progress to a systemic
inflammatory response affecting distant organs.

Studies have revealed a key role for phospholipase A2 in propagating this inflammatory
response by inducing the production of inflammatory mediators, including arachidonic acid
metabolites. Elevated levels of phospholipase A2 have been found in the serum of patients
with AP who develop severe complications, including pancreatic necrosis, shock, and OF. The
in vitro inhibition of phospholipase A2 using NSAIDs has been evaluated as a potential
treatment strategy for AP, with indomethacin shown to be the most potent inhibitor among 17
tested agents. NSAIDs also inhibit the interaction of neutrophils with endothelial cells,
thus preventing the accumulation of neutrophils at the site of injury.

In animal models of AP, NSAIDs have been shown to attenuate AP severity and improve survival.
Most human studies, however, have primarily assessed the role of NSAIDs in PEP prophylaxis. A
meta-analysis of 4 randomized, controlled studies evaluating this effect revealed a
protective role for these medications, and a recent multicenter, randomized controlled trial
found that administrating rectal indomethacin to patients at increased risk for PEP
significantly reduced the incidence and severity of pancreatitis. In 1985, a small randomized
controlled trial (n=30) of rectal indomethacin in patients with AP reported a significant
decrease in the duration of pain. This is the only study to date evaluating NSAIDs following
the onset of AP and did not evaluate systemic inflammation. The effect of rectal indomethacin
in mitigating disease progression in patients at risk for developing severe disease thus
remains to be evaluated.

SIRS is a simple clinical score, ranging from 0-4, that utilizes objective, routine clinical
parameters (body temperature, heart rate, respiratory rate or arterial carbon dioxide tension
and white blood count) that directly reflect the underlying inflammatory response. The
persistence of SIRS, defined by the presence of a SIRS score ≥2 at 48 hrs following
presentation, has been shown to be significantly associated with the development of OF,
pancreatic necrosis and death in patients with AP. Additionally, serum levels of CRP at 48
hours following admission have also been closely correlated with the development of OF.

Objective:

Our proposed randomized, double-blind, placebo-controlled pilot trial seeks to evaluate the
efficacy of rectal indomethacin in abrogating systemic inflammation in patients with acute
pancreatitis (AP) and systemic inflammatory response syndrome (SIRS).

Specific Aims:

Our long-term goal is to alter the clinical course of AP in patients who are at high risk for
the development of organ failure (OF) and death. The objective of this randomized,
double-blind, placebo-controlled pilot trial is to evaluate the efficacy of rectal
indomethacin on attenuating systemic inflammation in patients with AP who also have SIRS. The
investigators hypothesize that the treatment of patients with AP and SIRS with therapeutic
doses of rectal indomethacin will mitigate the inflammatory response through the inhibition
of inflammatory mediators. The investigators will also test the hypothesis by enrolling 42
patients randomized to receive either rectal indomethacin or placebo for 48 hours and
pursuing the following specific aims:

Aim 1. Evaluate the effect of rectal indomethacin on systemic inflammation as measured by the
change in mean SIRS score and serum CRP levels following 48hrs of treatment in patients with
AP and SIRS; and

Aim 2. Evaluate the impact of rectal indomethacin on the development of OF and mortality.

Significance:

The proposed study will thus be the first attempt at evaluating the therapeutic role of
NSAIDs in patients with AP and SIRS who are at high risk for the development of OF and for
whom no effective pharmacological therapy is currently available. Pilot data generated will
serve as a platform for a larger scale study that will validate the efficacy of indomethacin
in the treatment of AP.

Inclusion Criteria:

- All patients ages 18 or above admitted to UPMC with a diagnosis of AP based on at
least 2 of the following criteria:

(i) abdominal pain characteristic of AP (ii) serum amylase and/or lipase ≥ 3 times the
upper limit of normal (iii) characteristic findings of AP on abdominal CT scan will be
screened for study enrollment.

- Patients with SIRS (≥ 2 of the following criteria: temperature <36°C or >38°C, heart
rate >90/min, respiratory rate >20/min OR PaCO2<32 mmHg, WBC <4,000/mm3, >12,000/mm3
or >10% bands) upon hospital admission or who develop SIRS during their first week of
hospitalization

Exclusion Criteria:

- Presence of OF (shock defined by SBP<90mmHg, PO2<60mmHg on room air or need for
mechanical ventilation, Cr≥2mg/dL)

- Presence of renal dysfunction (Cr>1.5mg/dL)

- Active peptic ulcer disease

- Pregnancy

- Use of daily NSAIDs within 1 week of presentation

- Allergy to NSAIDs.