ABSTRACT There are currently limited medicinal interventions demonstrated to improve outcomes in patients with acute severe non-autoimmune pancreatitis, a highly morbid and potentially fatal condition which is estimated to afflict up to 275,000 patients annually in the US.[1] Early-stage mild pancreatitis often self-resolves; however 15-20% of cases [2] progress to a severe form characterized by a potentially lethal systemic inflammatory response syndrome with injury to multiple organs and (frequently) respiratory failure. Further clinical deterioration can lead to necrotizing pancreatitis, which is clinically similar to sepsis and has a reported mortality of up to 30%. [3–6] Although inflammation is known to be a key driver of disease progression, no anti-inflammatory therapy investigated to date has shown sufficient efficacy to become part of routine clinical practice. Identification of a viable medicinal therapy for severe acute pancreatitis thus remains a significant unmet need. In this application, we propose this need can be met via early delivery of a short course of physiologic-dose corticosteroids. This commonly used anti-inflammatory therapy has been shown to provide a clear patient benefit with other diseases which trigger systemic inflammation, multi-organ injury, and respiratory failure (e.g. sepsis, Acute Respiratory Distress Disorder (ARDS), and most recently COVID-19), but has been poorly studied in pancreatitis. The few published pilot trials of this therapy for severe acute pancreatitis have shown corticosteroids shorten the duration of shock and may improve mortality, but these results must be validated in a series of increasingly large, rigorous clinical trials before this therapy is widely accepted by clinicians. Here we propose the logical first step Phase II trial: a blinded, randomized clinical trial of an early physiological dose of hydrocortisone vs. placebo in 86 ICU patients with severe acute pancreatitis. The trial will be conducted by the nationally recognized critical care research team at the Center for Resuscitation Science. We hypothesize that corticosteroids will attenuate the inflammatory response from pancreatitis resulting in mitigated disease severity and organ injury. We secondarily hypothesize there will be a concomitant reduction in mortality, though this hypothesis will be the focus of a follow-up Phase III trial. After baseline assessments, enrollees will receive either 100 mgs of hydrocortisone or matching placebo intravenously in a blinded fashion every 8 hours for 72 hours (300 mg/day). The primary trial outcome will be the change in SOFA disease severity score over 72 hours, and from these data we will conduct a novel sub-study to determine if corticosteroid efficacy is better in specific subgroups whose clinical outcomes may be the most uncertain. Secondary outcomes will include progression to ARDS, ventilator- free days, ICU- and hospital-free days, inflammatory biomarker profiles, biomarkers for ...