Assessment of the Anti-inflammatory Effect of Heparin Infusion Versus Subcutaneous Injection in Septic Patients
Condition: Sepsis; Critical Illness
MeSH terms: Critical Illness
Study type: Interventional
Phase: Phase 2

Summary: 
      Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thrombosis
      (DVT), is a common and severe complication of critical illness. Critically ill patients are
      at high risk of VTE because they combine both general risk factors together with specific ICU
      risk factors of VTE. Vasopressor administration was found to be an independent risk factor
      for DVT. certainly explained by reduced absorption of subcutaneous heparin linked to the
      vasoconstriction of peripheral blood vessels. For critically ill patients, due to the altered
      pharmacokinetics behavior of unfractionated heparin, continuous intravenous infusion of the
      low doses of unfractionated heparin has been proposed. Standard prophylaxis with subcutaneous
      (SC) heparin is less efficient in patients requiring vasopressors. Sepsis is a systemic
      inflammatory response due to an infection. Both inflammatory mediators and coagulation are
      involved in sepsis. the release of inflammatory mediators such as interleukins and tumor
      necrosis factor causes damage to the endothelium and activation of coagulation which promotes
      the inflammatory process. Unfractionated heparin is the most negatively charged biological
      molecule known, heparin has a strong ability to interfere with the functioning of positively
      charged molecules. Due to the difference in charges, heparin has been documented to interact
      with over 100 proteins.57 Interleukins, cytokines, and receptors located on endothelial
      cells, which are involved in the acute phase response, are positively charged and thus are a
      reasonable target for the modulating effects of heparin. Heparin has strong anti-inflammatory
      effects with many possible mechanisms, including binding to cell-surface glycosaminoglycans,
      preventing leukocyte migration, direct binding to chemokines and cytokines, and inhibition of
      intracellular NF-kB.
    

Detailed description: 
      1. Ethical committee approval will be obtained from the Ethics Committee of the Faculty of
           Pharmacy, Damanhour University.

        2. All participants or their next kin should agree to participate in this clinical study
           and will provide informed consent.

        3. 40 participants who are critically ill with sepsis.

        4. The 40 participants will be randomly assigned into 2 groups:

             -  Standard care group: will be treated with subcutaneous heparin 5000 units three
                times daily for DVT prophylaxis.

             -  Experimental group: will be treated with heparin infusion 5000 unit\hour for DVT
                prophylaxis

        5. All patients will be subjected directly at the time of enrollment to the following:

             -  Full patient history and clinical examination.

             -  complete blood picture, liver function tests, and renal function tests.

             -  The initial cause of ICU admission and define the origin of the present infection.

             -  Complete cultures obtained urine, blood, and sputum.

             -  Coagulation profile (prothrombin time, prothrombin activity, international
                normalization ratio (INR), clotting time, and activated partial thromboplastin
                time).

             -  Arterial blood gases analysis (including hypoxic index).

             -  The severity of disease assessment using Acute Physiology and Chronic Health
                Evaluation version II (APACHE II) score.

             -  Organ failure assessment using Organ Failure Assessment (SOFA) score and quick
                (SOFA) score.

             -  Kidney assessment using Kidney Disease Improving Global Outcomes (KDIGO) criteria.

             -  Liver disease assessment using Child-Pugh Score.

             -  Chest radiography, electrocardiography, and transthoracic echocardiography.

             -  Vital signs (systolic blood pressure, diastolic blood pressure, heart rate,
                respiratory rate temperature, blood sugar level, and urine output).

        6. All patients will be monitored for the incidence of DVT, minor and major bleeding during
           their intensive care unit stay (ICU).

        7. Coagulation profile, serum lactate, serum electrolytes, hypoxic index,14-day mortality,
           and the following pro-inflammatory biomarkers will be measured at the start and at days
           1,2, and 7 of the study.

           i. CRP ii. Heparin-binding protein (HBP) iii. Plasminogen activator inhibitor (PAI).

        8. Patient demographic data will be recorded with respect to sex. age, weight, disease, and
           medication history.

        9. Statistical tests appropriate to the study design will be conducted to evaluate the
           significance of the results.

       10. Results, conclusion, discussion, and recommendations will be given.

       11. A p-value of less than 0.05 will be considered statistically significant.

       12. The study data were evaluated using IBM SPSS software (statistical product and service
           solution version 26.0)
    

Intervention name(s): Heparin Infusion; subcutaneous heparin
Intervention type(s): Drug; Other
Intervention description(s): 500 unit heparin infusion \ hour for DVT prophylaxis experimental group (n=20); 5000 unit subcutaneous heparin /8 hours control group n=(20)
Other intervention name(s): new regimen; conventional regimen
Intervention MeSH terms: Heparin; Calcium heparin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized Control Trial
Masking: Single (Participant)
Primary purpose: Prevention
Keywords: heparin infusion; DVT prophylaxis; Anti inflammatory