Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection

Xiangya Hospital of Central South University, Central South University, The Second Hospital University of South China, Wuhan Union Hospital, China, The Affiliated Yantai Yuhuangding Hospital of Qingdao University

Sepsis is the leading cause of death in intensive care units and a major public health concern in the world. Heparin, a widely used anticoagulant medicine to prevent or treat thrombotic disorders, has been demonstrated to prevent organ damage and lethality in experimental sepsis models. However, the efficacy of heparin in the treatment of clinical sepsis is not consistent. Caspase-11, a cytosolic receptor of LPS, triggers lethal immune responses in sepsis. Recently, we have revealed that heparin prevents cytosolic delivery of LPS and caspase-11 activation in sepsis through inhibiting the heparanase-mediated glycocalyx degradation and the HMGB1- LPS interaction, which is independent of its anticoagulant properties. In our study, it is found that heparin treatment could prevent lethal responses in endotoxemia or Gram-negative sepsis, while caspase-11 deficiency or heparin treatment failed to confer protection against sepsis caused by Staphylococcus aureus, a type of Gram-positive bacterium. It is probably that other pathogens such as Gram-positive bacteria might cause death through mechanisms distinct from that of Gram-negative bacteria. Peptidoglycan, a cell-wall component of Gram-positive bacteria, can cause DIC and impair survival in primates by activating both extrinsic and intrinsic coagulation pathways, which might not be targeted by heparin. We speculate that the discrepancy between the previous clinical trials of heparin might be due to the difference in infected pathogens. Thus, stratification of patients based on the type of invading pathogens might improve the therapeutic efficiency of heparin in sepsis, and this merits future investigations.

In clinical patients, the major pathogens of sepsis caused by abdominal infection are mostly Gram-negative bacterium. Therefore, aim of this study is to determine effects of low dose unfractionated heparin for treatment of sepsis caused by abdominal infection.

A bottle solution of Heparin Sodium (2ml:12500IU) is added to 48 ml saline and administered intravenously continuously for 24 hours (10 unit/kgBW/hour), which last 5 days or until the death or discharge.

The same amount of 0.9% saline as the heparin group (50ml) will be administered in the placebo group.

Total Sequential Organ Failure Assessment (SOFA) score(0-24) , higher values represent a worse outcome

Acute Physiology and Chronic Health Evaluation (include Acute physiology score, APS and age and Chronic physiology score, totally 0-71 Points)

Concentration of inflammation markers such as c-reactive protein, procalcitonin, IL-1β and IL-1α at 0, 3,6 days after randomization

Concentration of coagulation related indexes such as fibrinogen degradation products, d-dimer, thrombin-antithrombin complex, plasminogen activator inhibitor-1, plasmin antiplasmin complex, and thrombomodulin at 0,3,6 days after randomization

"Major bleeding" is defined as intracranial bleeding, life-threatening bleeding, or need red blood cell suspension more than 3 units every 24 hours, and last for 2 days

Inclusion Criteria: Patients will be eligible for inclusion if all of the inclusion criteria are met: 1.Sepsis-3 criteria from Society of Critical Care Medicine (SCCM) /European Society of Intensive Care Medicine (ESICM), and the infection site is from abdomen 2.18≤ age ≤75years 3.obtain informed consent Exclusion Criteria: The primary site of infection is from other parts (such as lungs, intracranial, etc.) except abdomen Diagnosis of sepsis for more than 48 hour Pregnant and lactating women Severe primary disease including unrespectable tumours, blood diseases and Human Immunodeficiency Virus (HIV); Have a known or suspected adverse reaction to UFH including HIT Have bleeding or high risk for bleeding Have an indication for therapeutic anticoagulation or have taken anticoagulants within 7 days Use of an immunosuppressant or having an organ transplant within the previous 6 months Participating in other clinical trials in the previous 30 days Have received cardiopulmonary resuscitation within 7 days Have terminal illness with a life expectancy of less than 28 days

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