The document summarizes various alternatives to blood transfusion, including oxygen carrying solutions, hemoglobin based oxygen carrying solutions (HBOCS), perflourocarbons, antigen camouflage techniques, recombinant plasma proteins, and transgenic platelet substitutes. It discusses the advantages and challenges of each approach, such as universal compatibility with oxygen carriers but side effects with HBOCS including vasoactivity and gastrointestinal issues.

1. Tranfusion Medicine Amanda J. Wheeler, MD Trauma/Critical Care Stanford University Medical Center May 7, 2007

2. Tranfusion Medicine “ The 1988 NIH Consensus Conference on Perioperative Red Blood Cell Transfusions suggested that no single criterion should be used as an indication for red cell component therapy and that multiple factors related to the patient's clinical status and oxygen delivery needs should be considered.”

3. Transfusion Triggers/Indications: Acute Blood Loss Crystalloids should be used to fluid resuscitate hypovolemic patients along with inotropic agents to maintain blood pressure and cardiac output. Oxygen delivery adequate because greater cardiac output, rightward shift of the oxygen-hemoglobin dissociation curve, and increased oxygen extraction can compensate for the decrease in arterial oxygen content. Need for transfusion based on rate of blood loss. >40% blood volume loss has been shown to require rapid transfusion as well as 30-40% loss after initial replacement with crystalloids.

4. Hemoglobin Concentration Hgb around 10 previously used as a trigger. Studies reviewing Jehovah’s Witnesses postop outcomes have shown that lower Hgb concentrations did not increase mortality. Animal models and retrospective studies have shown increased mortality at Hgb levels of 3.5-4.0g/dl. Notably, increase in the Lactate levels and the oxygen extraction ratio >50% were observed. However in animal models with cardiac disease, the increase in mortality was observed around Hgb levels of 6-7.5 g/dl. Canadian Critical Care Trial Group: study compared “restrictive” (Hgb<7) to “liberal” (Hgb<10) transfusion strategies among critically ill patients. The “restrictive” strategy was as effective and superior to the “liberal” transfusion strategy among patients less than 55 and without cardiac disease. Patients had an overall greater decrease in mortality and less complications. They concluded that a transfusion threshold of 7 g/dl is safe in critically ill patients, including those with minimal cardiopulmonary disease. Recent recommendations suggest RBC transfusion only in cases with <Hgb and known clinical

6. Blood Transfusion Protocol at Stanford Surgery ICU Committee: Susan Brundage, MD, MPH, Myriam Curet, MD, Rochelle Dicker, MD, Ralph Greco, MD , David Gregg, MD, John Morton, MD, MPH, Tom C. Nguyen, MD, MPH, Jeffrey Norton, MD, Andrew Shelton, MD, David Spain, MD, Mark Welton, MD, M. Lance Tavana, MS4. Background: There are divergent views on the risks of anemia and the benefits of blood transfusion in critically ill patients. Blood products are not without risk, and unnecessary blood transfusion contributes to increased morbidity, costs, and, in some studies, mortality. In an effort to promote decision consistency and reduce the number of inappropriate blood transfusions, an evidenced-based transfusion guideline should be employed. Indications: The major indication for RBC product transfusion is to prevent or treat symptoms of tissue hypoxia by augmenting the oxygen carrying capacity in blood. Principles: Patients should be informed of transfusion when possible. • In the setting of acute blood loss, transfusion should not be used to expand vascular volume when oxygen carrying capacity is adequate.

7. Blood Transfusion Protocol at Stanford Surgery ICU Refer to handout.

8. Massive Transfusion Guidelines Definition: Massive Transfusion is defined as replacement of at least one blood volume within the first 12 hours of resuscitation. Criteria for Activation of the MTG*: 1. Adult patients requiring > 4 units of PRBCs in first hour of resuscitation or pediatric patient requiring > 20 ml/kg of PRBCs in first hour of resuscitation. 2. Adult patients with the high likelihood of requiring transfusion of > 10 units of PRBCs within the first 12 hours of resuscitation or pediatric patient with the high likelihood of requiring transfusion of > 0.1 units/kg of PRBCs within the first 12 hours of resuscitation.

9. In general, one needs to evaluate the risk-benefit ratio of transfusion. There are no reliable parameters to decide on when to transfuse, especially when Hgb 7-10g/dl. One needs to use their clinical judgment and consider the following along with the above indications: Ability to compensate for anemia Rate of ongoing blood loss Likelihood of further blood loss Evidence of end-organ compromise Risk of CAD Balance of risks vs. benefits of transfusion

10. Other Alternatives: Blood Substitute Slides by Mary-Ann Purtill, MD Americans alone donate over 16 million units of blood yearly: Processed in 26 million units of PRBC and derivative products. 4.8 million Americans receive blood transfusions of various kinds Only 5% of the 60% of eligible donors give blood

11. Three primary reasons driving the quest for a substitute for Blood: Quantity Chronic shortages h/o “ooze for booze” leading to tainted blood products Red Cross now relies on volunteer donations Storage blood is perishable long and short term storage is an expensive problem Purity non-tainted blood of the correct blood type is not always available when needed.

12. Types of Replacement Products Oxygen Carrying Solutions Hemoglobin Based Oxygen Carrying Solutions (HBOCS) Perflourocarbons Other Antigen Camouflage Recombinant Plasma Proteins Transgenic Therapeutic Proteins Platelet Substitutes

13. Oxygen Carrying Solutions Hemoglobin Based Oxygen Carrying Solutions (HBOCS) Stroma free hemoglobin solutions Non-hemoglobin solutions perfluorocarbon emulsions

14. Oxygen Carrying Solutions Advantages include: Universally compatible No clerical errors Stored for long periods of time No prior planning Ready to use No waste No equipment Long shelf life No refrigeration Easily virally inactivated Available in the field for use in mass trauma situations Can be use by Jehovah's Witnesses

15. Hemoglobin Based Oxygen Carrying Solutions (HBOCs) 1916 purified Hgb first used to treat anemia Failed secondary to renal failure Stromal tissue containing endotoxins identified as the culprit High oxygen binding affinity of Hgb also diminished off-loading of oxygen to tissues Historical Perspective

16. Problems with HBOCS Vasoactivity nitric oxide binds to hemoglobin, less available to cause vascular smooth muscle relaxation Hemostasis increased hemostatic effect due to reversal of the inhibition effect of nitric oxide on platelet aggregation. Gastrointestinal side effects nausea, vomiting, diarrhea, and bloating nitrous oxide binding to gastrointestinal intestine tissues is the proposed cause. Interference with laboratory assays high concentrations of hemoglobin in plasma interferes with laboratory assays LFTs, bilirubin, amylase and others often yield inaccurate results Availability of hemoglobin molecules limited blood supply genetic engineering Immunologic response foreign Hgb causes poor immunologic responsecontinued chemical engineering to decrease the affinity Short Half-Life around 3 days Increased oxygen affinity

17. Comparison of HBOCs Hemolink PolyHeme Hemopure & Oxyglobin Product Name: 14 hours 24 hours 18-22 hours Half-life: Refrigerated/ RoomTemp Refrigerated Room Temp Storage: 1 year 1 year 3 years Shelf-life: Expired Human RBCs Expired Human RBCs Bovine Hgb Source: Hemosol Northfield Biopure

18. Perflourocarbon Oxygen Carriers Carry five times more oxygen More effective off-loading of oxygen at the tissue level Microdroplets that carry oxygen are 1/70th the size of the red cells reach many areas of the body that human RBCs cannot. The product is inert and can be fully sterilized removed from body over 4-12 hours via normal respiration Stored at room temperature NO type and cross-matching prior to use.

19. Perflourocarbon Oxygen Carriers (cont) Indications: “an all-purpose synthetic blood product” Surgery Trauma Angioplasty Open heart surgery Oxygenation of tumors during radiation or chemotherapy Easily available: on the battlefield at the scene of accidents stored in emergency vehicles and emergency departments. “ Oxycyte” and “Oxygent”

20. Problems with Perflourocarbons Side effects Phagocytosis of the PFCE particles causes flu-like symptoms Fever muscle aches Nausea Vomiting Hepatosplenomegaly Decrease in blood platelet count PFCE particles cannot be metabolized 18-24 months to remove all of the particles

21. Antigen Camouflage Camouflaging the surface of red blood cells Creates a universal blood type. Polyethylene glycol (PEG) Biocompatible polymer forms a permanent covalent bond on the surface of the cell Coating effectively hides the antigenic molecules on the surface of the red blood cells Antigenically unrecognized by recipient's antibodies, and therefore not destroyed

22. Antigen Camouflage Diseases requiring repeat blood transfusions often complicated by the development of antibodies to &quot;minor&quot; red cell antigens &quot;allosensitization&quot; can render these patients almost impossible to transfuse PEG-modified red cells do not trigger allosensitization potentially useful in clinical situations where allosensitization has already occurred. Though antigenically &quot;silent&quot; these modified red cells: structurally normal functionally normal normal survival time

23. Recombinant Plasma Proteins Can be made in unlimited quantities Specific deficient product replaced Free of blood-borne pathogens Factors VII, VIII and IV.

24. Transgenic Therapeutic Proteins Synthetic human proteins made in the milk of animals Human genes for coagulation factors protein C and factor VIII to date into pig embryos pigs synthesized the corresponding human proteins in their milk These can be purified for therapeutic use This model can serve as a source of other therapeutic proteins unlimited production low cost free of human pathogens

25. Platelet Substitutes Approximately 18 million units of platelets are transfused each year worldwide 80% goes to patients who are thrombocytopenic as a result of chemotherapy Chemotherapy regimes more aggressive Two products currently being tested: Synthocytes Infusible Platelet Membranes

26. Platelet Substitutes (cont) Synthocytes are microcapsules to which fibrinogen has been chemically linked act as a replacement for human blood platelets selectively targeting the site of hemorrhage &quot;Infusible Platelet Membranes&quot; fragment the membrane of outdated platelets extract key hemostatic components of platelets Factor 3 Glycoprotein 1b receptor reduces bleeding time in animal and humans with aspirin ingestion controls mucosal bleeding in thrombocytomenic patients refractory to platelet transfusions no antibodies to platelets were noted no significant toxicities