Studies of HBOC-201 in Animal Models of Hemorrhagic Shock BPAC - 14 December 2006 John R. Hess, MD, MPH, FACP, FAAAS COL, MC, US Army (Ret) Professor Pathology and Medicine Associate Medical Director, Blood Bank Medical Director, Stem Cell Lab Primary Investigator, U. Maryland National Transfusion Medicine/Hemostasis Clinical Trials Network, NHLBI

U.S. Army HBOC program Spent $100 million to explore basic science and seed field. First cross-linked hemoglobin in 1968 Explored chemistry of Hb modification Produced sterile HbA 0 and ααHb Explored toxicology (identified 6 forms) Closed program when public investment reached $2 billion and toxic effects ignored

U.S. Army Swine Physiology Program 1974-present Spent $100 million to explore basic science and test techniques and products. Researchers: P Hannon, C Wade, P Maningus, W Bickle, J Hess, J Holcomb Products: –Replaced dog as major large animal model –Resuscitation fluids (HS-D, etc) –Hypotensive resuscitation –Hemoglobin toxicity –Hemorrhage control drugs and devices

Basic Rules for Swine Physiology Pigs are relatively anemic with a normal hematocrit = 30%. Pigs are sensitive to oxidative injury. Pigs drop their blood pressure more than humans in response to hemorrhage. Pigs die when their hematocrit reaches 9% in the absence of alternative oxygen carriers.

Navy KO04-04 Protocol Evaluation of HBOC-201 in Uncontolled Hemorrhage and Traumatic Brain Injury Pigs were given fluid percussion brain injury and 50% left lower lobe liver injury. Resuscitated with nothing, LR at 20mL/15 min, or HBOC at 10ml/15 min 30 minute delay in “hospital” treatment led to no significant differences 75 minute delay in “hospital” treatment led to increased deaths in untreated and LR groups

Navy KO04-04 Protocol Evaluation of HBOC-201 in Uncontolled Hemorrhage and Traumatic Brain Injury Liver and brain injured swine resuscitated with nothing, HBOC or large volumes of LR. LR group does well until 75 minutes.

Navy KO04-04 Protocol Evaluation of HBOC-201 in Uncontolled Hemorrhage and Traumatic Brain Injury Fluid drives hemorrhage and hemodilution so that the pigs arrive a the fatal Hct of 9 at 75 minutes

Navy KO04-04 Protocol Evaluation of HBOC-201 in Uncontolled Hemorrhage and Traumatic Brain Injury LR treated pigs get 20ml/kg x 4 equivalent to giving you 6 quarts of fluid

Navy KO04-04 Protocol Evaluation of HBOC-201 in Uncontolled Hemorrhage and Traumatic Brain Injury The model does not reflect current thinking about volume administration in the brain- injured. The model does not test the efficacy of the HBOC against equivalent volumes of the fluid it comes in. It knowingly sets up a condition that kills the control animals.

King, Cohn, & Proctor, J Trauma 2005 Resuscitation with a hemoglobin-based oxygen carrier after traumatic brain injury Comparison of large volume LR with small volume HBOC Controls get equivalent of 20 liters of LR

King, Cohn, & Proctor, J Trauma 2005 Resuscitation with a hemoglobin-based oxygen carrier after traumic brain injury Extra volume leads to brain swelling and bad outcome in the LR group

King, Cohn, & Proctor, J Trauma 2005 Resuscitation with a hemoglobin-based oxygen carrier after traumic brain injury The model does not reflect current thinking about volume administration in the brain- injured. The model does not test the efficacy of the HBOC against equivalent volumes of the fluid it comes in. The model does not test the efficacy of the HBOC against modern therapy.

Studies of HBOC-201 in Animal Models of Hemorrhagic Shock The studies did not address physiologically useful questions about known toxicities of HBOCs. The models do not test the efficacy of the HBOC against equivalent volumes of the fluid it comes in. The models were designed show off the HBOC, not to test it critically.