Tuc m UT iieto mac ue rec PM RUM Re aac Teele Ly Adapted from: Philip Abraham et al. Efficacy and Safety of Intravenous ulinastatin versus Placebo along with Standard Supportive Carein Subjects with Mild or Severe Acute Pancreatitis. Journal of the association of physicians of India; August 2013,vol 61 Ulinastatin, found in human urine and blood is a serine protease inhibitor. Trypsin inhibitors exert a localized anti-inflammatory effect and suppress the proteolytic action of trypsin on a variety of tissues. Ulinastatin attenuates the elevation of neutrophil elastase release, thereby blunting the rise of pro- inflammatory cytokines and also inhibits secretion of pro-inflammatory cytokines IL-6 and IL-8. The present study which was a randomized, double-blind, placebo-controlled, multicentre trial across 15 centres in India, evaluated the effect of addition of ulinastatin to standard care on mortality and morbidity in Indian subjects with acute pancreatitis. Mom = Individuals, aged 18 to 70 years, with acute pancreatitis and elevated serum C-reactive protein (CRP) levels, were eligible for enrolment. = Acute pancreatitis was diagnosed if the patient had at least two of the following conditions: ™ Suggestive abdominal pain Serum amylase and/or lipase > 3 times upper limit of normal = Imaging findings of acute pancreatitis = On the bi of the APACHE II score (< 8 mild, > 8 severe) subjects were classified as having mild or severe acute pancreatitis. = Eligible subjects were randomized to receive intravenous infusion of 200,000 IU ulinastatin or placebo in 100 ml of 0.9% saline given over one hour every 12 hours for 5 days. SS ™ The study reported that out of the 135 randomized subjects, 129 completed the study (mild 62, severe 67). ™ In 81% ofthe subjects alcohol consumption was the major cause of pancreatitis, = Lpatientin the ulinastatin group vs. 6 in the placebo group died of severe pancreatitis (p = 0.048). = New organ dysfunction developed in 5 ulinastatin vs. 4 placebo group subjects (p = 0.744) with mild pancreatitis and 12 in ulinastatin and 29 in placebo subjects (p=0.0026) with severe pancreatitis. = Significantly lower incidence of adverse events were noted in subjects with severe pancreatitis in the ulinastatin group as compared to the placebo group (p = 0.00001).Prtacieteg meta hca nected Mild pancreatitis aoe Uiinastatin Placebo (n= 30) (32) Mortality (n) 163%) ° Newonset organ, (yetunction No. ©) 5.067%) 4.025%) ‘Adverse events 3B 35 Serum CRP (x ULN) . Day 7 median (1OR) 226(01-1448) 11.17 (03-1453) Serum CRP change Derby RednageRy — 1552G1217-1354) 846 (70-112) Hospital stay (days) 5. . then oon) 76-2) 86-15) LULN: Upper limit of normal QR: interquartile range; CRP: C-reactive protein Conclusion prvalue as ozs 082 0942 0344 0074 Severe pancreatitis Uiinastatin Placebo value (a= 35) 30 P 128%) 6as7%) 004s 12G43%) —-29(906%) 0.0026 B 45 00000129, 121-430) 10(03-165) 071 aobly9 99024-16907. 96-22) 106-22) 0207 This study concluded that ulinastatin not only reduces mortality in subjects with severe pancreatitis but also prevents new organ dysfunctionEfficacy of intravenous ulinastatin in treatment of patients with Raa hy Adapted from: Kamnad D R et al. Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: multicenter randomized controlled study, Intensive Care Med. 10.1007/500134-014-3278-8, A frequent cause of morbidity and mortality in critically ill patients is that of sepsis and evidence records increasing incidence annually. Recent studies have indicated that the systemic inflammatory response syndrome (SIRS) that characterizes severe sepsis results from an excessive activation of proinflammatory mediators. These have pleiotropic effects that overpower the bodys anti- inflammatory mechanisms and thus, lead to widespread vascular, endothelial and organ dysfunction thatis often fatal. The intermediaries involved in the systemic inflammatory processes are serine proteases. In the presence of inflammation the liver produces several protease inhibitors to counter-regulate the effect of these proteases. Experimental studies have indicated that a serine protease inhibitor, ulinastatin, inhibits several pro-inflammatory proteases and decreases inflammatory cytokine levels and mortality. The present study evaluated the effect of ulinastatin on 28-days all-cause mortality in a double-blind trial in patients with severe sepsis in seven Indian hospitals. (eee = Within 48 hours of onset of one or more organ failures, patients with sepsis were randomized to receive intravenous administration of ulinastatin (200,000 IL) or placebo 12 hourly for days. eee = The study reported that out of 122 randomized subjects, the study was completed by 114 patients (55 received ulinastatin, 59 received placebo). = Atbaseline, the mean APACHE Il score was 13.4 (SD = 4. 48 (42%) patients were receiving mecha 58 (51%) were on vasopressors 35% had multiple organ failure = The primary end-point ofthis study (28-day mortality) showed a significant difference in the two ‘treatment groups Four deaths (7.3%) were reported in the ulinastatin group as opposed to 12 deaths (20.3%) in the placebo group. = Stepwise multiple logistic regression analysis revealed that treatment with ulinastatin produced a statistically significant decrease in risk of death. m= Lower incidence of new onset organ failure (10 vs. 26 patients, p = 0.003), more ventilator-free days (mean «SD 19.4 « 10.6 days vs. 10.2 12.5 days, p= 0.019) and shorter hospital stay (11.8 7.1 days vs. 24.2 = 7.2 days, p <0.001) was reported in the ulinastatin group.20% 15% 10% 05% 0% 13% reduction in Mortality 20.3% 73% 28 Day all cause Mortality 1m Ulinastatin ml -Placebo 26% Reduction in New Onset Organ Dysfunction 44% a | New Onset Organ Dysfunction 50% 40% 30% 20% 10% 00% m Ulinastatin ml Placebo mortality rate in patients 25 50% Increase in Ventilator Free Days 1m Ulinastatin 10.20 Ventilator Free Days m Placebo Pemes N Results of this pilot study, revealed that intravenous administration of ulinastatin reduced ith severe sepsis in the modified intention-to-treat analysis.