Outcome of Ulinastatin vs Metabolic Resuscitation using Ascorbic Acid, Thiamine and Glucocorticoid in Early Treatment of Sepsis- A Randomised Controlled Trial

Introduction: Sepsis is one the most common cause of morbidity and mortality worldwide. Sepsis and septic shock are life-threatening disease which increases mortality with circulatory, cellular and metabolic abnormalities. Urinary trypsin inhibitor is an important protease inhibitor found in human blood and urine, it is known as Ulinastatin (ULI) or bikunin. It is an acidic glycoprotein (molecular weight 30 kDa) and Kunitz-type serine protease inhibitor. It is derived from the larger inter-α-trypsin inhibitor molecule by action of neutrophil elastase in the presence of inflammation, and is believed to play an important anti-inflammatory role. Aim: To compare the outcome of intravenous ULI (protease inhibitor known as urinary trypsin inhibitor) versus the combination of hydrocortisone, ascorbic acid (vitamin C) and thiamine regarding outcome in sepsis and septic shock. Materials and Methods: In this randomised controlled trial conducted between July 2018 to June 2019 on total 60 sepsis patients were included and divided into two equal groups. Group A patients received combination of intravenous Hydrocortisone, Ascorbic acid and Thiamine (HAT) and group B Ulinastatin received intravenous Intensive Care Unit(ICU). Baseline demographic, clinical and laboratory data were recorded along with Acute Physiology and Chronic Health Evaluation (APACHE) 2 and Sequential Organ Failure Assessment (SOFA) scoring system at the time of admission in ICU. All statistical test were performed using SPSS 21.0 windows software. Comparisons between groups were assessed by using student t-test and chi-square test. Results: Mean age was comparable in both the groups (36.7±12.5 years in group A vs 37.5±12.9 years in group B). SOFA Score were significantly lower in group B as compared to group A on day 3 (7.76±3.67 vs 12.03±4.77) and day 5 (4.79±4.02 vs 12.10±7.36). Rate of reduction in serum procalcitonin level was also found to be significant in group B (p=0.008) as compared to group A (p=0.103). Lactate clearance rate was also fast in group B as compared to group A on day 3 and day 5. There was significant mortality benefit in group B (20%) as compared to group A (50%). Patients were followed up for 28 days till the start of treatment. Conclusion: This study showed that the ULI may play a beneficial role in early management of sepsis and septic shock.

The Protective Roles of Urinary Trypsin Inhibitor in Brain Injury Following Fat Embolism Syndrome in a Rat Model

Fat embolism syndrome (FES) is a common complication following long bone fracture; fat droplets are released into the blood circulation and form embolisms, mainly in lung and brain. However, the potential mechanisms involved remain to be clarified. In this study, the mechanism of brain injury following FES and the protective effects of urinary trypsin inhibitor (UTI)—a serine protease inhibitor—were investigated. Sixty male Sprague-Dawley rats were divided randomly into sham, FES and FES+UTI treatment groups. The FES model was established using tail vein injection of glycerol trioleate, and UTI was administered by intraperitoneal injection immediately following FES. Brain/lung water content evaluation, Evans blue content and magnetic resonance imaging examination were used to assess the effects of UTI. Furthermore, immunohistochemistry and western blot were also applied to explore the protective mechanism of UTI following FES. The results of oil red O staining indicated that the FES model was successfully established. UTI could significantly attenuate blood-brain-barrier (BBB) disruption, as seen through brain edema evaluation and Evans blue content examination. Immunofluorescence staining results indicated that the TLR4-JNK pathway was involved in brain injury after FES; this effect could be quenched by UTI treatment. Furthermore, UTI could decrease the levels of downstream target proteins of the TLR4-JNK pathway, phosphorylated-NF- κB (p65) and p53 in brain. Our results showed that UTI could alleviate BBB injury after FES through blocking activity of the TLR4-JNK pathway.

Levels of Urinary Trypsin Inhibitor and Structure of Its Chondroitin Sulphate Moiety in Type 1 and Type 2 Diabetes

Background. Diabetes mellitus is a global health problem representing the fifth leading cause of mortality and a major risk factor for cardiovascular diseases. In the last years, we reported an association among urinary trypsin inhibitor (UTI), a small proteoglycan that plays pleiotropic roles in many inflammatory processes, and both type 1 and 2 diabetes and developed a method for its direct quantitation and structural characterization. Methods. Urine from 39 patients affected by type 1 diabetes, 32 patients with type 2 diabetes, and 52 controls were analysed. UTI was separated from the main glycosaminoglycans physiologically present in urine by anion exchange chromatography, treated for chondroitin sulphate (CS) chain complete depolymerisation, and analysed for both UTI content and CS structure. UTI identification was performed by nano-LC-MS/MS analysis. Results. We evidenced increased UTI levels, as well as reduced sulphation of its CS moiety in association with diabetes, regardless of both age and medium-term glycaemic control. Furthermore, no association between UTI and albumin excretion rate was found. Conclusions. Evidences suggest that UTI levels are not directly correlated with renal function or, otherwise, that they may increase before the onset of renal impairment in diabetes, representing a potential marker for the underlying inflammatory condition.

Effect of Ulinastatin in the Treatment of Postperative Cognitive Dysfunction: Review of Current Literature

Background.Ulinastatin, identified as a urinary trypsin inhibitor, has been widely used in patients with inflammatory disorders. However, little is known about its effect on postoperative cognitive dysfunction (POCD). The aim of our current work is to review the current body of literature.Methods.A systematic literature search in PubMed and EMBASE was performed to identify randomized controlled trials. Incidence of POCD, MMSE score, and laboratory indicators (IL-6, TNF-α, CRP, and S100β) were selected as outcomes.Results.Five RCTs involving 461 elderly patients that underwent surgical operations were identified. The meta-analysis suggested no statistical difference of incidence of POCD between ulinastatin and control groups on postoperative day 1; but ulinastatin could significantly decrease the incidence of POCD on postoperative day 3 and day 7 when compared with control treatment. Ulinastatin was effective in improving the MMSE score on day 1, day 3, and day 7 after operation. IL-6 and S100βconcentrations were lower up to postoperative day 2. The incidences of postoperative complications in ulinastatin groups were lower than control.Conclusion.Ulinastatin administration was effective in treating early POCD (postoperative day 3 and day 7) and reducing IL-6 and S100βconcentrations within two days after operations. Studies with larger-scale and rigorous design are urgently needed.