Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection

Sponsor

The Third Xiangya Hospital of Central South University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04861922

Collaborator

(none)

100

Enrollment

Location

Arms

27.3

Anticipated Duration (Months)

3.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis Gram-Negative Bacterial Infections Heparin	Drug: Unfractionated Heparin	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study

Anticipated Study Start Date :

Apr 20, 2021

Anticipated Primary Completion Date :

Apr 30, 2023

Anticipated Study Completion Date :

Jul 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Unfractionated Heparin 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.	Drug: Unfractionated Heparin 10 unit/kgBW/hour continuous infusion for 5 days Other Names: Heparin sodium
Placebo Comparator: Normal saline The same amount of 0.9% saline as the heparin group (50ml) will be administered in the placebo group.	Drug: Unfractionated Heparin 10 unit/kgBW/hour continuous infusion for 5 days Other Names: Heparin sodium

Arm

Intervention/Treatment

Experimental: Unfractionated Heparin

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.

Drug: Unfractionated Heparin

10 unit/kgBW/hour continuous infusion for 5 days

Other Names:

Heparin sodium

Placebo Comparator: Normal saline

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

Drug: Unfractionated Heparin

10 unit/kgBW/hour continuous infusion for 5 days

Other Names:

Heparin sodium

Outcome Measures

Primary Outcome Measures

All-Cause Mortality [28 Days after randomization]
Death from all causes at 28-days

Secondary Outcome Measures

Death in ICU [28 Days after randomization]
Death from all causes at ICU discharge
SOFA score [Day 0,3,6 after randomization]
Total Sequential Organ Failure Assessment (SOFA) score(0-24) , higher values represent a worse outcome
APACHEⅡ [Day 0,3,6 after randomization]
Acute Physiology and Chronic Health Evaluation (include Acute physiology score, APS and age and Chronic physiology score, totally 0-71 Points)
SIC score [Day 0,3,6 after randomization]
Sepsis-induced coagulopathy score (totally 0-6 Points)
DIC score [Day 0,3,6 after randomization]
Disseminated intravascular coagulation score (totally 0-8 Points)
Duration of mechanical ventilation and continuous renal replacement therapy [28 days after randomization]
Duration of mechanical ventilation and continuous renal replacement therapy in ICU
ICU stay [28 days after randomization]
Duration of stay in ICU
Inflammation [0,3,6 days after randomization]
Concentration of inflammation markers such as c-reactive protein, procalcitonin, IL-1β and IL-1α at 0, 3,6 days after randomization
Coagulation [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
The incidence of major bleeding [28 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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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