Safety of Heparin 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.

• 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 aPTT 40-50 seconds
  Patients 11-15: IV heparin, target aPTT range 40-50 seconds
  Intervention: Drug: heparin
• Experimental: intravenous heparin
  Patients 26-40: IV heparin, target range aPTT 50-60 seconds
  Interventions:

  • Drug: heparin
  • Drug: heparin
• Experimental: Intravenous heparin
  Patients 41-55 IV heparin, target aPTT range 60-70 seconds
  Interventions:

  • Drug: heparin
  • Drug: heparin
• Active Comparator: sq heparin three times a day
  Patients 1-10 will receive subcutaneous heparin three times a day
  Intervention: Drug: heparin

• Marshall JC. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med. 2001 Jul;29(7 Suppl):S99-106. Review.
• 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. 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.
• Robertson MS. Heparin: the cheap alternative for immunomodulation in sepsis? Crit Care Resusc. 2006 Sep;8(3):235-8. Review.
• 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.

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 -