In a recent issue of Intensive Care Medicine (ICM), Karnad et al.[1] reported a randomized, double-blind, placebo-controlled multicenter trial (RCT) evaluating the efficacy of a urinary protease inhibitor (ulinastatin) compared to placebo in patients with severe sepsis. This RCT was conducted in the intensive care units (ICUs) of seven tertiary care hospitals in India including 114 patients. Patients received intravenous ulinastatin or placebo twice daily for 5 days. Ulinastatin was associated with significantly decreased mortality (7.3 vs. 20.3%, P= 0.042), with 25% of the deaths in the ulinastatin group judged related to ARDS compared to 42% in the placebo group, lower frequency of new organ dysfunction, and shorter durations of mechanical ventilation and hospital stay compared to placebo. Furthermore, in stepwise multiple logistic regression (adjusted for age, gender, GCS, specific organ failures, number of organ failures, need for vasopressor, and mechanical ventilation), treatment with ulinastatin was associated with a statistically significant decrease in mortality. This is an interesting trial with quite impressive results given the relatively small sample size, which raises these questions: what is ulinastatin and why might it be important in sepsis?

Ulinastatin (UTI) is a multifunctional Kunitz-type serine protease inhibitor found in human urine and blood. UTI (also known as ulinastatin, HI-30, ASPI, or bikunin) is produced by hepatocytes and belongs to a group of proteins known as the inter-o-inhibitor (IoI) family. During inflammation, ulinastatin is cleaved from IoI family proteins through proteolytic cleavage by neutrophil elastase in the peripheral circulation or at sites of inflammation. Ulinastatin inhibits various serine proteases that are important in the pathophysiology of sepsis including trypsin, thrombin, chymotrypsin, kallikrein, plasmin, elastase, cathepsin, and factors IXa, Xa, XIa, and XIIa. Ulinastatin also inhibits inflammation by suppressing the infiltration of neutrophils and release of elastase and inflammatory mediators from neutrophils. Ulinastatin also inhibits the production of TNF-o, IL-1, and IL-6 possibly through suppression of MAPK signalling pathway [2].