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.

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)

Inclusion Criteria:

• Adults Patients aged 18 years old or greatecritically ill patients aged 18-65 years diagnosed with sepsis/septic shock or developed sepsis/septic shock during their ICU length of stay were enrolled.

Exclusion Criteria:

-Thrombocytopenia, Intracerebral hemorrhage at the time of sepsis Bleeding tendency (INR ≥ 1.5 or PLT < 50 x 109/L,) Medical condition requiring therapeutic anticoagulation Age < 18 years Previous history of Heparin Induced Thrombocytopenia (HIT).

single (Participant)