Blood Substitutes for Hemorrhagic Shock

1. Blood Substitutes for Hemorrhagic Shock Matthew Zuckerman, M4 Medical Therapeutics University of Michigan Medical School

2. Why Important Moore: Shock, Volume 24(3).September 2005.197-205

3. Where Important Moore: Shock, Volume 24(3).September 2005.197-205

4. History of Blood Substitutes • 1st Generation: Pure hemoglobin • Stripping RBC membranes should avoid rejection • Effects: Renal failure, hypertension, bradycardia • 2nd Generation: Polymerized hemoglobin • Crosslinking to avoid renal effects • Unstable reaction products are heterogeneous • 3rd Generation: Intra-molecular cross-link • Extremely vasoactive; trials halted • 4th Generation • Custom molecules Semin Hematol. 2007 Jan;44(1):51-9.

5. History of Blood Substitutes • Take-Home Point: • Therapeutic advances are often step-wise and filled with numerous failures before finding something that works • The number of failed attempts at something is not related to its ultimate chance of success (e.g. the history of flight) Semin Hematol. 2007 Jan;44(1):51-9.

6. First Generation Trials • Study: Phase I safety trial • Stroma-free hemoglobin administered to 8 healthy males • 7/8 did fine, but 1/8 developed • abdominal pain and CVA tenderness • Patients also developed decrease in urine outputandcreatinine clearance • Other reports of renal failure and vasoactive responses (hypertension, bradycardia) led to 2nd generation blood replacement products Clin Pharmacol Ther. 1978 Jan;23(1):73-80.

7. Polyheme Does a Body Good J Am Coll Surg. 2002 Oct;195(4):445-52

8. Polyheme Trial • Study: Prospective, randomized Phase II trial • Compare PolyHeme to RBCs in hemorrhage • Population: 44 trauma patients (33 male, 11 female) aged 19–75 years • Inclusion criteria • blood loss because of acute trauma or urgent operation, • anticipated transfusion due to low Hb or hypovolemic hypotension (SBP < 100) • Exclusion criteria • Severe head injury (GCS<9) • Lack of hemorrhage • Pregnancy J Am Coll Surg. 1998 Aug;187(2):113-20

9. Polyheme Trial • Results • RBC [Hb] fell to 5.8 ± 2.8 g/dL vs. 10.6 ± 1.8 g/dL (p < 0.05) in the control (makes sense with cell free preparations) • Total [Hb] was not different between the groups or from pre-infusion • Strengths • Positive outcome with increased total Hb and decreased need for transfusion of RBC’s • Weaknesses • Not totally blinded, small N, phase II trial • Since Polyheme is a blood product, it doesn’t necessarily increase the initial supply of blood but does allow use of blood products for one year, increasing the total pool J Am Coll Surg. 1998 Aug;187(2):113-20

10. Another Polyheme Trial • Trial: Cohort study, compares 30-day mortality in patients receiving PolyHeme with a historical control group of patients who declined blood transfusion for religious reasons • Total of 171 patients received rapid infusion of 1 to 2 units (n = 45), 3 to 4 units (n = 45), 5 to 9 units (n = 47), or 10 to 20 units (n = 34) of PolyHeme J Am Coll Surg. 2002 Oct;195(4):445-52

11. Another Polyheme Trial J Am Coll Surg. 2002 Oct;195(4):445-52

12. Another Polyheme Trial • RBC Hb dropped to nadirs of Forty patients had a nadir 3 g/dL (mean, 1.5 ± 0.7 g/dL). • Total [Hb] was adequately maintained (mean, 6.8 ± 1.2 g/dL) • 30-day mortality was 25.0% (10/40 patients) compared with 64.5% (20/31 patients) in historical control patients at these RBC [Hb] levels J Am Coll Surg. 2002 Oct;195(4):445-52

13. Another Polyheme Trial • Strengths • Polyheme was able maintain total Hb in patients, allowing them to avoid RBC transfusion • Polyheme demonstrated lower mortality than historical controls who declined blood transfusions (and presumably received crystalloid) • Weaknesses • Small N • Lack of blinding, randomization, or prospective control group • Historical controls can often demonstrate worse outcomes than prospective studies due to improvements in medical care (e.g. everyone does better than they would have years ago) • Historical controls were more likely to be older, female, and have different indications for transfusion than prospective polyheme subjects J Am Coll Surg. 2002 Oct;195(4):445-52

14. Another Polyheme Trial • The paper attempts to address the concern over variation in prospective and control groups saying: • “Common demographic and medical characteristics in the treatment and historical control groups were age, ASA physical status score, cardiovascular risk or history, date of admission, gender, race, and hospital site. Although the two groups differed on all of these parameters, supportive modeling determined that none of these parameters altered the outcome of the original analysis. The important similarity is the progressive blood loss in the surgical setting unaccompanied by red cell replacement.” • In other words, we know they are different, but we don’t think it matters. All that matters is that they were bleeding • This is a gutsy, but questionable assertion, especially given that none of the “supportive modeling” is in the paper J Am Coll Surg. 2002 Oct;195(4):445-52

15. Pre-hospital Polyheme Trial • Randomized, controlled open-label, multi-center Phase III study of patients in hemorrhagic shock • Had pre-hospital and hospital phases • En route, randomized subjects receive either saline or Polyheme • Upon arrival at the hospital • Polyheme group continues to receive polyheme for up to 12 hours • Control group begins to receive RBCs at hospital • Study involved waiving informed consent Northfield Labs Press Release, December 19 2006

16. Pre-hospital Polyheme Trial • Analysis of preliminary results • Primary efficacy endpoint of the study is Day 30 mortality in the modified intent to treat population • 30 day mortality in Polyheme group was 10.8% (30/279); while control group was 9.1%(28/307) • Initial data indicated that benefits from Polyheme did not meet the required threshold • Polyheme still announced its intention to submit a Biologics License Application Northfield Labs Press Release, December 19 2006

17. FDA Policy: Skipping Consent • Permissible when all of below is true • Life threatening situation with unsatisfactory available treatments • Obtaining informed consent is not feasible • Participation may directly benefit subjects • Study can’t be done practically without a waver • Set window of time, during which attempts to contact patient representative is made • IRB has approved • Additional protection of subject rights: community consultation, public disclosure, independent data monitoring, consent is obtained as soon as possible 61 Federal Register 51528, Oct. 2, 1996 Moore: Shock, Volume 24(3).September 2005.197-205

18. Polyheme Controversy • Popular press reports were appalled that any study could be done without informed consent (reminiscent of Tuskegee) • Ethicists questioned the underlying ethics as well as adherence to FDA guidelines • Ambulance portion appeared ethical as RBC’s are unavailable and consent is impossible • Hospital portion was controversial as RBC’s are available • Additionally, many felt the multicenter study failed to properly inform the communities Am J Bioeth. 2006 May-Jun;6(3):18-21.

19. Polyheme Controversy • Northfield Labs justified the hospital portion of the study, siting the advantages of polyheme over RBC’s due to: • “adverse immunomodulatory effects of early blood transfusion in trauma patients, specifically the incidence of multiple organ failure and the resultant associated mortality.” • Additionally, Northfield argued the benefit of immediately available oxygen carrying fluid (like Polyheme) that does not need to be cross-matched Northfield Labs Press Release, March 14, 2006

20. Informed Consent? What’s that? • Survey was given to patients in ED where Polyheme trial was going on and community meetings had taken place • Only 6.9% of respondents were aware of the study (this increased to 8.8% after the negative media reports) • Of these 39: 13 gained awareness through television, 12 from newspapers, 4 each through word of mouth and meetings, and 2 each from radio and Internet. Several listed more than one source • At 6 to 12 weeks after public notification, only half of the 39 were able to list one or more risks associated with the study Acad Emerg Med.2007; 14: 187-191

21. Polyheme Controversy • Survey was given to patients in ED where Polyheme was going on and community meetings had taken place • Responses to the statement that benefits outweigh risks of emergency research with exception from informed consent were notably positive • Participants' views about taking part in such research themselves, or about a family member's participation, also did not reflect compelling acceptance (just because they agree in theory, doesn’t mean they want to be the guinea pig) • Men were almost twice as amenable to personal or family participation as women (interpret as you will) Acad Emerg Med.2007; 14: 187-191

22. Clinical Readiness • Currently, it appears that blood substitutes are not ready for prime time • Polyheme may be helpful in isolated areas without blood supplies available (assuming they can pay the great cost of fake blood) • Most physicians have been using crystalloid and RBC’s and are comfortable with them; any new product is going to have to demonstrate effectiveness to change people’s minds

23. Clinical Readiness • Research on substitutes will continue due to • The incredible need for stable, readily available, universal, disease free blood substitutes (here and especially abroad) • The incredible profit available to companies who come up with a viable product • This research will continue to be difficult due to the ethical dilemmas involved in consent as well as appropriate controls (crystaloid vs RBC’s vs historical)

24. Future directions • New blood products will hopefully prove more effective than Polyheme • FDA will be revisiting its rules on consent waivers in the near future