Safety of Heparin in Patients With Septic Shock

Safety of Heparin Anticoagulation for Prevention of Death in Patients With Septic Shock.

Sepsis is a syndrome comprised of a systemic inflammatory response, signs of tissue hypoperfusion, and organ in the setting of presumed infection. Heparin, in addition to being an anticoagulant, is also a well-known antiinflammatory. The investigators believe that unfractionated heparin has the potential to save the lives of septic patients at a drastically reduced cost. This is a dose escalation study to determine the safety of increasing levels of heparin in this patient population; compare markers of anticoagulation and inflammation between treatment groups; and compare clinical outcomes between groups.

Study Overview

• Status: Withdrawn
• Conditions: Sepsis
• Intervention / Treatment: Drug: heparin; Drug: heparin; Drug: heparin; Drug: heparin

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-90 in the medical or surgical intensive care unit
2. Within 24 hours of diagnosis with sepsis as defined by the Bone criteria (see Appendix A);
3. Acute Physiology and Chronic Health Evaluation (APACHE II) score of > 25;
4. Signed consent

Exclusion Criteria:

1. Currently therapeutically anticoagulated for known thrombotic diagnosis (myocardial infarction, venous thromboembolism) known molecular hypercoagulable state (Factor V Leiden, lupus anticoagulant, antiphospholipid antibody syndrome); or use of cardiopulmonary support machines (left-ventricular assist device, intra-aortic balloon pump, veno-venous ultrafiltration, or extracorporeal membrane oxygenation.
2. History of gastrointestinal or cerebral hemorrhage within past 3 months;
3. Active bleeding;
4. Known allergy or sensitivity to heparin;
5. History of heparin-induced thrombocytopenia
6. Organ transplantation recipient -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intravenous heparin aPTT 40-50 seconds; Patients 11-15: IV heparin, target aPTT range 40-50 seconds	Drug: heparin; intravenous heparin titrated to an aPTT of 40-50 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 50-60 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 40-45 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; 5000 units subcutaneously three times a day, starting within 24 hours of ICU admission up to 6 days.
Experimental: intravenous heparin; Patients 26-40: IV heparin, target range aPTT 50-60 seconds	Drug: heparin; intravenous heparin titrated to an aPTT of 40-50 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 50-60 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 40-45 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; 5000 units subcutaneously three times a day, starting within 24 hours of ICU admission up to 6 days.
Experimental: Intravenous heparin; Patients 41-55 IV heparin, target aPTT range 60-70 seconds	Drug: heparin; intravenous heparin titrated to an aPTT of 40-50 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 50-60 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 40-45 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; 5000 units subcutaneously three times a day, starting within 24 hours of ICU admission up to 6 days.
Active Comparator: sq heparin three times a day; Patients 1-10 will receive subcutaneous heparin three times a day	Drug: heparin; intravenous heparin titrated to an aPTT of 40-50 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 50-60 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; intravenous heparin titrated to an aPTT of 40-45 seconds starting between 300-500 units per hour and adjusted every 6 hours based on aPTT, starting within 24 hours of ICU admission up to 6 days.; Drug: heparin; 5000 units subcutaneously three times a day, starting within 24 hours of ICU admission up to 6 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of major bleeding	Defined as:decrease in hemoglobin greater than 2g/dl and/or transfusion of 2 or more units of packed red blood cells. However, if there are obvious other reasons for bleeding, such as within 12 hours of major surgery, coagulopathy unrelated to heparin or an anatomical basis.	This outcome will be measured for an average of 30 days

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Sara Cheng, MD;PhD, University of Colorado, Denver

Publications and helpful links

General Publications

• Marshall JC. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med. 2001 Jul;29(7 Suppl):S99-106. doi: 10.1097/00003246-200107001-00032.
• Agarwal R, Gupta D. Anticoagulation in sepsis: is low-dose heparin as effective as activated protein C? Intensive Care Med. 2005 Sep;31(9):1297-8. doi: 10.1007/s00134-005-2723-0. Epub 2005 Jul 9. No abstract available.
• Zarychanski R, Doucette S, Fergusson D, Roberts D, Houston DS, Sharma S, Gulati H, Kumar A. Early intravenous unfractionated heparin and mortality in septic shock. Crit Care Med. 2008 Nov;36(11):2973-9. doi: 10.1097/CCM.0b013e31818b8c6b.
• Robertson MS. Heparin: the cheap alternative for immunomodulation in sepsis? Crit Care Resusc. 2006 Sep;8(3):235-8.
• Derhaschnig U, Pernerstorfer T, Knechtelsdorfer M, Hollenstein U, Panzer S, Jilma B. Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med. 2003 Apr;31(4):1108-12. doi: 10.1097/01.CCM.0000059441.70680.DC.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Anticipated): April 1, 2013
• Study Completion (Anticipated): October 1, 2013

Study Registration Dates

• First Submitted: September 23, 2010
• First Submitted That Met QC Criteria: November 3, 2010
• First Posted (Estimate): November 4, 2010

Study Record Updates

• Last Update Posted (Estimate): May 20, 2014
• Last Update Submitted That Met QC Criteria: May 19, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: intensive care unit; septic shock; sepsis; anticoagulation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: 10-0595