1. The risk of Severe DIAR in Trauma Patients given HSD Eileen M. Bulger, MD Associate Professor of Surgery Co-PI Resuscitation Outcomes Consortium

2. Hypertonic Saline Dextran 7.5% saline/6% dextran-70, 250cc given as initial resuscitation fluid for patients with hypovolemic shock 7.5% saline/6% dextran-70, 250cc given as initial resuscitation fluid for patients with hypovolemic shock Approved in 14 European countries, Rescueflow, Biophausia Inc, Sweden Approved in 14 European countries, Rescueflow, Biophausia Inc, Sweden 8 previous clinical trials,meta-analysis demonstrates improved survival OR 1.47 and 2 fold increase in survival for patients with traumatic brain injury 1,2 8 previous clinical trials,meta-analysis demonstrates improved survival OR 1.47 and 2 fold increase in survival for patients with traumatic brain injury 1,2

3. Advantages of HSD Resuscitation 3 More rapid restoration of perfusion with small volume More rapid restoration of perfusion with small volume Improved cerebral perfusion while decreasing intracranial pressure Improved cerebral perfusion while decreasing intracranial pressure May alter the response of the immune system after injury: May alter the response of the immune system after injury: Decrease the risk of developing lung injury (ARDS) by inhibiting neutrophil and monocyte activation Decrease the risk of developing lung injury (ARDS) by inhibiting neutrophil and monocyte activation Reduce nosocomial infection by enhanced T cell function Reduce nosocomial infection by enhanced T cell function

4. Current & Proposed Trials Current trial at University of Washington Current trial at University of Washington Phase 2 trial, primary endpoint ARDS Phase 2 trial, primary endpoint ARDS Current enrollment 205pts, now on clinical hold Current enrollment 205pts, now on clinical hold Proposed ROC trial Proposed ROC trial Phase 3 trial, n=3018 Phase 3 trial, n=3018 Hypovolemic shock- 28 day survival Hypovolemic shock- 28 day survival Traumatic Brain Injury- Neurologic outcome Traumatic Brain Injury- Neurologic outcome

5. Resuscitation Outcomes Consortium NIH NIH NHLBI NHLBI NINDS NINDS CIHR CIHR US DOD US DOD Canadian DOD Canadian DOD

6. Limitations of Prior reports of DIAR Elective surgery, older population (mean age 60yrs), high rate w/ epidural or spinal anaesthesia Elective surgery, older population (mean age 60yrs), high rate w/ epidural or spinal anaesthesia Relies on comparison to historical controls from 1970-1979 Relies on comparison to historical controls from 1970-1979 No randomized controlled trial data available No randomized controlled trial data available

7. Risk of Severe DIAR in Trauma patients Experience with HSD Experience with HSD 900 pts in clinical trials, 20,100pts treated in Europe 900 pts in clinical trials, 20,100pts treated in Europe NO REPORTS OF DIAR NO REPORTS OF DIAR 0/21000, < 5/100,000 0/21000, < 5/100,000 Estimates based on Hypertonic hetastarch experience: 4-8/100,000 4.5 Estimates based on Hypertonic hetastarch experience: 4-8/100,000 4.5

8. Comparison of Risk for Severe DIAR Trauma pts receiving HSD 0-4/100,000 Historical controls: Ljungstrom et al 6,7 25-50/100,000 Historical controls: Ring et al 8 8/100,000 Promit premedication (20cc) Ljungstrom et al 9,10 1.4-3/100,000 Annual anaphylaxis risk in community 11 21/100,000

9. Why Trauma patients may be protected? High circulating levels of catecholamines High circulating levels of catecholamines Rapid infusion of the solution may result in an excess of antigen in the blood and thus prevent the formation of immune complexes. Rapid infusion of the solution may result in an excess of antigen in the blood and thus prevent the formation of immune complexes.

10. Limitations of Promit Side effects: 1-57/100,000 9,10 Side effects: 1-57/100,000 9,10 Skin reactions Skin reactions Bradycardia +/- hypotension Bradycardia +/- hypotension Hypotension Hypotension HSD most effective as first fluid given HSD most effective as first fluid given Premedication may delay medic from other critical interventions Premedication may delay medic from other critical interventions Feasibility in prehospital or battlefield setting Feasibility in prehospital or battlefield setting Immuno-modulatory effects of Promit are unknown. May interfere with the effectiveness of HSD Immuno-modulatory effects of Promit are unknown. May interfere with the effectiveness of HSD

11. Summary Trauma patients receiving HSD at much lower risk of severe DIAR than previous reports. Trauma patients receiving HSD at much lower risk of severe DIAR than previous reports. To date no reports of DIAR with 21,000 patients receiving HSD. To date no reports of DIAR with 21,000 patients receiving HSD. There is no statistical difference between the estimated risk of severe DIAR for trauma patients receiving HSD and the projected risk with Promit pre-treatment for dextran infusion. There is no statistical difference between the estimated risk of severe DIAR for trauma patients receiving HSD and the projected risk with Promit pre-treatment for dextran infusion. We ask the committee to consider whether Promit premedication should be required in this circumstance. We ask the committee to consider whether Promit premedication should be required in this circumstance.

12. References 1. Wade C, Grady J, Kramer G. Efficacy of hypertonic saline dextran (HSD) in patients with traumatic hypotension: meta-analysis of individual patient data. Acta Anaesthesiol Scand Suppl 1997;110: 77-9 2. Wade C, Grady J, Kramer G et al. Individual patient cohort analysis of the efficacy of hypertonic saline/dextran in patients with traumatic brain injury and hypotension.1997 J Trauma 42:S61-5 3. Svensen C, Hypertonic Solutions: an update. ITACCS 2002, 6-12 4. Schimetta W, Schochl H, Kroll W et al. Safety of hypertonic hyperoncotic solutions-a survey from Austria. Wien Klin Wochenschr 2002, 114:89-95. 5. Barron ME, Wilkes MM, Navickis RJ. A systematic review of the comparative safety of colloids. Arch Surg 2004, 139:552-563 6. Ljungstrom KG, Renck H, Standberg K et al. Reactions to dextran in Sweden 1970-1979. Acta Chir Scand 149: 253-262, 1983. 7. Hedin H, Ljungstrom K. Prevention of dextran anaphylaxis: ten years experience with hapten dextran. Int Arch Allergy Immunol 1997, 113:358-359. 8. Ring J,Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitute. Lancet, 1977466-469. 9. Renck H, Ljungstrom K, Hedin H et al. Prevention of dextran-induced anaphylactic reactions by hapten inhibition. Acta Chir Scand 149:355-360, 1983. 10. Ljungstrom K, Willman B, Hedin H. Hapten inhibition of dextran anaphylaxis. Nine years of post-marketing surveillance of dextran 1. Ann Fr Anesth Reanim 12:219-222, 1993. 11. Yocum MW, Butterfield JH, Klein JS et al. Epidemiology of anaphylaxis in Olmsted County: a population-based study. J allergy Clin Immunol, 1999 104:452-457