Clinical Efficacy of Ulinastatin for Treatment of Sepsis With Systemic Inflammatory Response Syndrome

This completed multicenter randomized trial enrolled 120 adults with sepsis and systemic inflammatory response syndrome (SIRS). After informed consent, the enrollment day was Day 0. Participants were randomly assigned 1:1:1 to an ordinary-dose group, a high-dose group, or a placebo control group, and baseline clinical information was collected.

The ordinary-dose group received ulinastatin 400,000 units intravenously every 8 hours. The high-dose group received ulinastatin 800,000 units intravenously every 8 hours. The control group received an equal volume of 0.9% saline (50 mL) intravenously every 8 hours. When SIRS criteria were no longer met, the assigned dose (or matching placebo volume) was halved and continued; treatment lasted at least 3 days and up to 7 days.

Inclusion criteria

• Adults ≥18 and ≤80 years of age; 2) sepsis according to Sepsis-3; 3) sepsis diagnosis <48 hours; 4) SIRS; 5) written informed consent from the patient or a legally authorized representative.

Exclusion criteria

• Congestive heart failure with NYHA class IV function, cerebrovascular accident or acute coronary syndrome within 3 months, in-hospital or recent (within 7 days) cardiac arrest, non-infectious cardiogenic shock, or uncontrolled acute bleeding; 2) severe chronic liver disease (Child-Pugh C), liver parenchymal disease with significant portal hypertension, or acute liver failure; 3) chronic renal failure with dialysis before enrollment; 4) severe coagulopathy (ISTH DIC score ≥5); 5) significant immune impairment (organ or bone marrow transplantation; moderate or severe leukopenia within 3 months before screening, e.g. neutrophils <1.5×10^9/L; radiotherapy or chemotherapy within 3 months; HIV seropositivity; active hematologic or lymphatic malignancy); 6) Xuebijing, thymosin, or gamma globulin within 3 months before enrollment; 7) allergy to study drug, pregnancy, lactation, participation in another clinical trial within 3 months, or other conditions judged by the investigator to preclude participation.

Follow-up visits were on days 0, 1, 3, 5, 7, and 28. The primary outcome is the change in Sequential Organ Failure Assessment (SOFA) score from baseline to Day 5 (ΔSOFA). Secondary outcomes include SOFA at other visits, 28-day all-cause mortality, ICU stay, duration of antibiotics, SIRS, vasoactive drugs, mechanical ventilation and CRRT, and laboratory measures of infection, inflammation, coagulation, liver and kidney function, neurological and mental status, and endothelial injury.

Inclusion criteria

• sepsis-3 specified by SCCM and ESICM 1) suspected or confirmed infection: diagnosed by a clinician 2) evidence of acute organ dysfunction: for patients without chronic organ dysfunction in the past (assuming a baseline SOFA score of 0): sofa ≥ 2 points from 48 hours before diagnosis of infection to 24 hours after diagnosis of infection for patients with chronic organ dysfunction in the past (SOFA score should be based on baseline): the increase of sofa ≥ 2 points from 48 hours before diagnosis of infection to 24 hours after diagnosis of infection
• diagnosis of sepsis for less than 48 hours
• Systemic inflammatory response syndrome (SIRS) 1) body temperature > 38 ℃ or < 36 ℃ 2) heart rate > 90 3) respiratory rate> 20 4) WBC count > 12 × 10 ^ 9 / L or < 4 × 10^9/L (>12000/ μ L or < 4000/ μ L or immature granulocytes > 10%)
• Obtained informed consent signed by the patient or authorized immediate family member

Exclusion criteria

• Congestive heart failure (NYHA heart function level 4), cerebrovascular accident or acute coronary syndrome within 3 months, cardiac arrest within 7 days of this hospitalization, non-infectious cardiogenic shock, uncontrolled acute bleeding
• Severe chronic liver disease (Child-Pugh grade C), liver parenchymal lesions with obvious portal hypertension, acute liver failure
• Chronic renal failure, received dialysis treatment before being selected
• Severe coagulation function: ISTH-DIC score ≥ 5 points
• Significant immune abnormality/injury: received organ or bone marrow transplantation within 3 months before screening, moderate to severe leukopenia such as neutrophils <1.5×10^9/L, received radiotherapy or chemotherapy within 3 months , HIV seropositivity, active blood/lymphatic system tumor
• Have received Xuebijing, thymosin or gamma globulin treatment within 3 months before being selected for the study
• Others: allergies to study drugs, pregnancy, breast-feeding, participating in other clinical trials within 3 months, and other conditions deemed unsuitable by the investigator.