Therapeutic Hypothermia for Severe Acute Pancreatitis

Background: Acute pancreatitis is characterized by a high mortality rate (10%-15%), and a
remarkably unpredictable clinical course. Approximately 50% of deaths in acute pancreatitis
occur early—within the first 14 days—and early mortality is attributable to sequelae of a
severe systemic inflammatory response syndrome (SIRS), which is associated with multi-organ
dysfunction syndrome (MODS) that can escalate to renal failure, respiratory failure, and
death. Significant improvements in acute pancreatitis mortality will demand innovative
approaches to counteract early organ failure. A series of destructive cellular processes
begins within minutes of initial pancreatic injury, and the ensuing inflammatory cascade is
compounded by disease sequelae including edema, ischemia, and tissue necrosis. Early
interventions to reduce inflammation within the first 36 hours have been shown to have
significant effects in minimizing progressive organ dysfunction.

Hypothermia is clinically employed to combat cellular injury and systemic responses
following ischemia-reperfusion, and is been studied as a mechanism of acute inflammatory
inhibition in processes including cardiogenic shock, lung injury, local intestinal injury,
and reperfusion injuries to the lung, liver, and endothelium. In numerous studies, effective
immunomodulations have been observed including reduction of pro-inflammatory cytokines
(TNF-α, IL-6), stimulation of anti-inflammatory cytokines (IL-10), inhibition of
pro-apoptotic JNK signaling, reduction of systemic oxidative stress, and inhibition of
neutrophils, monocytes, and monocyte-derived macrophages. Most saliently, in the caerulein
model of murine acute pancreatitis, therapeutic hypothermia has been shown to reduce serum
IL-1, IL-6, and TNF-α, increased serum IL-10, decrease serum amylase and lipase, lower the
histological grade of pancreatic injury as compared to normothermic mice, and significant
survival benefit. Although therapeutic hypothermia is actively employed in the treatment of
traumatic brain injury, neonatal asphyxia, spinal cord injury, and cardiac arrest, no
studies have yet been made of its application to acute pancreatitis.

Hypothesis: Patients treated with therapeutic hypothermia (32-34°C) will sustain reduced
organ-specific injury in acute pancreatitis.

Proposal: In a Phase IIa pilot clinical trial, we will examine the effects of therapeutic
hypothermia on organ-specific outcomes during the early stage of acute pancreatitis. We will
recruit five patients aged 18 to 80 receiving medically-necessitated ventilator support
under ICU monitoring with core temperatures ≥36°C and severe acute pancreatitis defined as
either a Ranson Score ≥7, a CT indicating ≥50% pancreatic necrosis, or a significant
deterioration in clinical status including dysfunction of two or more organ systems (defined
by ACCP/SCCM Organ Failure Guidelines, Chest 2009). All patients will receive current
standard management for severe acute pancreatitis and a standardized protocol for
application of therapeutic hypothermia and rewarming. Our primary endpoints are
organ-specific cardiovascular, respiratory, hematological, renal, and metabolic dysfunction
as measured at 28 days. Logistic Organ Dysfunction Scores (LOD) will be compared before and
after therapeutic hypothermia, establishing day 4 versus day 1 changes in LOD. Secondary
endpoints include D-dimer, IL-6, C-reactive protein, APACHE II scores on day 1 and day 4,
inpatient and ICU length-of-stay, infection, mortality, and hypothermia-associated side
effects including cardiac arrhythmia, electrolyte imbalance, hyperglycemia, major bleeding,
and acute pancreatitis. We believe that such a study will supply preliminary answers to our
chief research questions: does therapeutic hypothermia reduce morbidity as assessed by
organ-specific outcomes, does therapeutic hypothermia attenuate the steep rise in
inflammation observed in severe acute pancreatitis, and does therapeutic hypothermia shorten
the clinical course for these patients.