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| Name | Class |
|---|---|
| Xiangya Hospital of Central South University | OTHER |
| Central South University | OTHER |
| The Second Hospital University of South China | OTHER |
| Union Hospital, Tongji Medical College, Huazhong University of Science and Technology |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Unfractionated Heparin | Experimental | 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. |
|
| Normal saline | Placebo Comparator | The same amount of 0.9% saline as the heparin group (50ml) will be administered in the placebo group. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Unfractionated Heparin | Drug | 10 unit/kgBW/hour continuous infusion for 5 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| All-Cause Mortality | Death from all causes at 28-days | 28 Days after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Death in ICU | Death from all causes at ICU discharge | 28 Days after randomization |
| SOFA score | Total Sequential Organ Failure Assessment (SOFA) score(0-24) , higher values represent a worse outcome |
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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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Zhijun Huang, MD | Contact | 0086-13908472564 | xy3gcp@163.com |
| Name | Affiliation | Role |
|---|---|---|
| Hong Yuan, MD | The third Xiangya Hospital, Central South University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The third Xiangya Hospital, Central South University | Recruiting | Changsha | Hunan | 410013 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33561388 | Background | Tang Y, Wang X, Li Z, He Z, Yang X, Cheng X, Peng Y, Xue Q, Bai Y, Zhang R, Zhao K, Liang F, Xiao X, Andersson U, Wang H, Billiar TR, Lu B. Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties. Immunity. 2021 Mar 9;54(3):454-467.e6. doi: 10.1016/j.immuni.2021.01.007. Epub 2021 Feb 8. | |
| 30314759 |
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| ID | Term |
|---|---|
| D018805 | Sepsis |
| D016905 | Gram-Negative Bacterial Infections |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D006493 | Heparin |
| ID | Term |
|---|---|
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
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| OTHER |
| Yantai Yuhuangding Hospital | OTHER |
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| Day 0,3,6 after randomization |
| APACHEⅡ | Acute Physiology and Chronic Health Evaluation (include Acute physiology score, APS and age and Chronic physiology score, totally 0-71 Points) | Day 0,3,6 after randomization |
| SIC score | Sepsis-induced coagulopathy score (totally 0-6 Points) | Day 0,3,6 after randomization |
| DIC score | Disseminated intravascular coagulation score (totally 0-8 Points) | Day 0,3,6 after randomization |
| Duration of mechanical ventilation and continuous renal replacement therapy | Duration of mechanical ventilation and continuous renal replacement therapy in ICU | 28 days after randomization |
| ICU stay | Duration of stay in ICU | 28 days after randomization |
| Inflammation | Concentration of inflammation markers such as c-reactive protein, procalcitonin, IL-1β and IL-1α at 0, 3,6 days after randomization | 0,3,6 days after randomization |
| Coagulation | 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 | 0,3,6 days after randomization |
| The incidence of major bleeding | "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 | 28 days after randomization |
| Deng M, Tang Y, Li W, Wang X, Zhang R, Zhang X, Zhao X, Liu J, Tang C, Liu Z, Huang Y, Peng H, Xiao L, Tang D, Scott MJ, Wang Q, Liu J, Xiao X, Watkins S, Li J, Yang H, Wang H, Chen F, Tracey KJ, Billiar TR, Lu B. The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis. Immunity. 2018 Oct 16;49(4):740-753.e7. doi: 10.1016/j.immuni.2018.08.016. Epub 2018 Oct 9. |
| 31836429 | Background | Yang X, Cheng X, Tang Y, Qiu X, Wang Y, Kang H, Wu J, Wang Z, Liu Y, Chen F, Xiao X, Mackman N, Billiar TR, Han J, Lu B. Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure. Immunity. 2019 Dec 17;51(6):983-996.e6. doi: 10.1016/j.immuni.2019.11.005. Epub 2019 Dec 10. |
| 32016282 | Background | Yang X, Cheng X, Tang Y, Qiu X, Wang Z, Fu G, Wu J, Kang H, Wang J, Wang H, Chen F, Xiao X, Billiar TR, Lu B. The role of type 1 interferons in coagulation induced by gram-negative bacteria. Blood. 2020 Apr 2;135(14):1087-1100. doi: 10.1182/blood.2019002282. |
| 31492850 | Background | Lu Y, Meng R, Wang X, Xu Y, Tang Y, Wu J, Xue Q, Yu S, Duan M, Shan D, Wang Q, Wang H, Billiar TR, Xiao X, Chen F, Lu B. Caspase-11 signaling enhances graft-versus-host disease. Nat Commun. 2019 Sep 6;10(1):4044. doi: 10.1038/s41467-019-11895-2. |
| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |