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The aim of this study was to study the development of early and late organ failure (OF) and their differential impact on mortality in patients with acute pancreatitis (AP).Consecutive patients (N = 805) with acute pancreatitis were included in an observational study. Organ failure was categorized as primary if it occurred early due to pancreatitis per se and secondary if it occurred late due to infected pancreatic necrosis (IPN). Primary outcome was a relative contribution of primary OF, secondary OF, and IPN to mortality.Of the 614 patients (mean age, 38.8; standard deviation, 14.6 years; 430 males) in a derivation cohort, 274 (44.6%) developed OF, with 177 having primary OF and 97 secondary OF due to sepsis. Primary OF caused early mortality in 15.8% and was a risk factor for IPN in 76% of patients. Mortality in patients with primary OF and IPN was 49.5% versus 36% in those with IPN and secondary OF (P = 0.06) and 4% in those with IPN but without OF (P < 0.001). The results of the 191 patients in the validation cohort confirmed the relative contribution of primary and secondary OF to mortality.Primary and secondary OF contributed to mortality independently and are distinct in their timing, window of opportunity for intervention, and prognosis.