1. Blood, but Not as we Know it: Blood Substitutes Anthony Holley Staff Intensivist Royal Brisbane & Womens Hospital

2. Declarations Mathew Davey Grant ADF Frozen Blood Working Group CLIP Trial Investigator SMACC Gold 14 3. The Challenge! 4. SMACC Gold 14 5. The Challenge 27,000 The number of blood donations needed by Australia every week! 500 000 The number of voluntary unpaid donors in Australia. 1.35 million The number blood donations collected in the 2010-2011 financial year by the Blood Service 2 The number of seconds between transfusions in the USA SMACC Gold 14 6. Why Blood Substitutes? Risk Availability Convenience SMACC Gold 14 7. SMACC Gold 14 8. SMACC Gold 14 9. SMACC Gold 14 10. Blood Coagulation OxygenVolume 11. The Contenders 12. Chemicals.. 13. 0 1 2 3 4 5 6 7 100 200 300 400 500 600 700 PFC 2.4g/dl PFC 1.6g/dl Plasma dissolved O2 SMACC Gold 14 PaO2 mmHg O2Contentml/100ml Dissolved Oxygen Content in Blood 14. Pros Inexpensive Easily manufactured Storage SMACC Gold 14 15. Clinical Practice SMACC Gold 14 16. Cons Requires FiO2 Complement activation and cytokine release Influenza-like syndrome Sequestration of platelets Viscosity at high [C] SMACC Gold 14 17. Carriers.. O2 18. Haemoglobin Based Oxygen Carriers 19. Haemoglobin A Tetrameric structure 22 4 subunits Heme moiety + polypeptide SMACC Gold 14 20. Haemoglobin Based Oxygen Carrier SMACC Gold 14 21. Sources of Haemoglobin SMACC Gold 14 22. Oxygen Dissociation Curves 0 20 40 60 80 100 120 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Partial Pressure of Oxygen PaO2 (mmHg) OxygenSaturation(%) RBC Hb Stroma Free Hb0 HBOC Hemospan P50 = 10 Hemolink P50 = 34 Hemopure P50 = 36 PolyHeme P50 = 26 23. SMACC Gold 14 24. Haemodynamic Response to Fluid response in Haemorrhaging Swine Hess et el. Systemic and Pulmonary hypertension after resuscitation with cell-free haemoglobin. 1993. J Appl Physiol 74: 1769- 1773SMACC Gold 14 25. SMACC Gold 14 Nanobiotechnology 26. Haemoglobin Modifications Antioxidant Enzymes 27. SMACC Gold 14 28. SMACC Gold 14 29. Vasoconstriction Nitric oxide scavenging Molecular size Endothelin Viscosity Oxygen affinity 30. SMACC Gold 14 31. Other Concerns SMACC Gold 14 Free radical generation Iron deposition macrophage function Antigenicity 32. Patients endangered in 'secret science' trials of risky blood substitutes 28th April 2008 SMACC Gold 14 33. Safety of HBOCs 1980 2008 70 trials 16 trials 5 products n =3711 34. SMACC Gold 14 35. SMACC Gold 14 36. SMACC Gold 14 Polyhemoglobin-Fibrinogen (polyHb-Fg). 37. SMACC Gold 14 38. Conditions 39. Deep Frozen Blood Deep Frozen Blood 40. The Advantage 41. SMACC Gold 14 42. The Netherlands A-80C Frozen blood products since 1993 43. Cryopreservation 44. Cryopreservatives Glycerol Dimethyl Sulfoxide 45. SMACC Gold 14 46. Cryopreserved vs. Liquid Platelets (CLIP) A pilot randomised, controlled, blinded clinical trial of cryopreserved platelets vs. conventional liquid-stored platelets for the management of post-surgical bleeding 90 cardiac surgical patients in 3 hospitals (TPCH, RPAH, Austin) Supported by ANZCA ($94K) and ARCBS ($50K) grants Will facilitate NH&MRC project grant application in 2014. 47. Lyophilised Platelets SMACC Gold 14 48. Components. 49. SMACC Gold 14 50. Platelet Derived Microparticles SMACC Gold 14 Infusible platelet membranes Thrombospheres Liposome Based Agents 51. Summary A real need! The contenders: Chemicals- Perfluorocarbons Carriers Haemoglobin Based Oxygen Carriers Conditions Lyophilised and Frozen platelets Components Platelet microparticles, Fibrinogen, Prothrombinex, Factors The future? 52. Thank You SMACC Gold 14 53. HemopureTM Polymerised bovine Hb Approved for use in South Africa 2001 Clinical use to treat acute anaemia and as alternative to donated blood in transfusion HemolinkTM Cross-linked human Hb Phase III trials completed Abondoned- unexpected cardiac toxicity HemospanTM Conjugated human Hb Phase Ib/II initiated in Sweden 2003 Published 2006 Anesthisiology Phase III recruiting Prevent hypotension in arhroplasty with spinal anaesthesia PolyHeme Polymerised pyridoxilated hemoglobin Trauma study n = 720 Ethical concerns re trial consent OptroTM Cross-linked Hb from genetically modified E. coli bacteria Phase II trials completed Trials completed in patients undergoing surgery in 1999 Haemoglobin Based Oxygen Carriers SMACC Gold 14