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This study aimed to conduct a single-center prospective trial of short-term continuous high-volume hemofiltration (HVHF) in patients with predicted severe acute pancreatitis (SAP).Patients with acute pancreatitis with Acute Physiology and Chronic Health Evaluation II scores of greater than 15 on admission between January 2008 and December 2010 were allocated to receive either optimal standard therapy or 72 hours of continuous HVHF on an alternate basis, beginning as soon as possible after admission. Biomarkers and clinical outcomes were compared between the 2 groups.A total of 61 patients received either conventional therapy (n = 29) or HVHF (n = 32). High-volume hemofiltration treatment was associated with a significant reduction in the incidence of renal failure (P = 0.013), infected pancreatic necrosis (P = 0.048), length of hospitalization (P = 0.005), mortality (P = 0.033), as well as duration of renal (P < 0.001), respiratory (P = 0.002), and hepatic failure (P = 0.001). Acute Physiology and Chronic Health Evaluation II score and C-reactive protein and interleukin 6 levels were significantly reduced after the start of HVHF on days 1, 3, and 7 (all, P < 0.05).This study suggests that short-term HVHF may reduce local and systemic complications and mortality in patients with SAP with Acute Physiology and Chronic Health Evaluation score of greater than 15.