P759760-Introduction.qxd 9/13/05 7:10 PM Page 2 Seetharama A.Acharya (39), Albert Einstein Univ. School of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA Paul Aebersold (3), Division of Blood Applications, Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Abdu I.Alayash (18), Center for Biologics Evalua- tion and Research – NIH Campus, FDA, Bethesda, MD, USA Vibhu Awasthi (43), University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Andrew D. Baines (20), Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada Ann L. Baldwin (22), Department of Physiology – College of Medicine, University of Arizona, Tucson, AZ, USA Andrea Bellelli (29), Dipartimento di Scienze Bio- chimiche, Universita ‘La Sapienza’, Rome, Italy Jan Blumenstein (41), Dextro-Sang Corporation, Toronto, Canada Liudmila A. Bogdanova (26), The Institute of Theoretical and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia William S. Brinigar (32), Department of Chemistry, Temple University, Philadelphia, PA, USA Maurizio Brunori (29), Dipartimento di Scienze Biochimiche, Universita ‘La Sapienza’, Rome, Italy Enrico Bucci (42), Biochemistry and Molecular Biology, University of Maryland Medical School, Baltimore, MD, USA Kenneth E. Burhop (23), Medication Delivery, Baxter Healthcare Corporation, Deerfield, IL, USA Pedro Cabrales (7, 8), Department of Bioengi- neering, University of California, San Diego, La Jolla, CA, USA Thomas Ming Swi Chang (38, 45), Faculty of Medicine, McGill University, Montreal, Quebec, Canada Keith W. Chapman (40), Sangart Inc., and Depart- ment of Bioengineering, University of California, San Diego, California, USA. Pierre-Guy Chassot (14), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Felice D’Agnillo (19), Division of Hematology, Center for Biologics, Evaluation and Research Food and Drug Administration, NIH Campus, Bethesda, MD, USA Randal O. Dull (32), Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA Barbara L. Ellington (21), Department of Neuro- surgery, University of California San Francisco and San Francisco Veterans Affairs Hospital, San Francisco, CA, USA Bengt Fagrell (17), Department of Medicine, Karolinska Sjukhuset, Stockholm, Sweden John A. Frangos (8), La Jolla Bioengineering Insti- tute, La Jolla, CA, USA Clara Fronticelli (32), Anesthesiology and CCM, Johns Hopkins University, Baltimore, MD, USA Maria S. Gawryl (36, 37), Research and Develop- ment, Biopure Corporation, Cambridge, MA, USA Elizabeth A. Goins (43), Department of Radiol- ogy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA J. David Hellums (6), Department of Bio- engineering, Rice University, Houston, TX, USA Hirohisa Horinouchi (46), Department of General Thoracic Surgery, School of Medicine, Keio Uni- versity, Tokyo, Japan List of Contributors P759760-Prelims.qxd 9/14/05 10:31 AM Page ix Yubin Huang (46), Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Marcos Intaglietta (7, 8), Department of Bioengi- neering, University of California, San Diego, La Jolla, CA, USA Bahram I. Islamov (26), The Institute of Theoreti- cal and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia Henrikh R. Ivanitsky (26), The Institute of Theoretical and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia Paul C. Johnson (9), Department of Bioengineer- ing, University of California, San Diego, La Jolla, CA, USA Natalia B. Karmen (26), The Institute of Theoretical and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia Peter E. Keipert (28), Sangart Inc., Sorrento Valley, San Diego, CA, USA Gregor Kemming (15, 16), Clinic of Anesthesiol- ogy and Institute for Surgical Research, Ludwig- Maximilian-University, Munich, Germany Harvey G. Klein (2), Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA Koichi Kobayashi (44, 46), Department of Surgery, School of Medicine, Keio University, Tokyo, Japan Raymond C. Koehler (21, 32, 42), Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA Teruyuki Komatsu (46), Advanced Research Insti- tute for Science and Engineering, Waseda Uni- versity, Tokyo, Japan Marie Pierre Krafft (24), Colloïdes et Interfaces, Institut Charles Sadron, Strasbourg, France George C. Kramer (12), Department of Anesthesiol- ogy and Physiology, University of Texas Medical Branch, Galveston, TX, USA Herman Kwansa (42), Department of Biochemistry and Molecular Biology, University of Maryland Medical School, Baltimore, MD,USA Laurence Landow (3), Division of Blood Applica- tions, Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Kimberly Lindsey (3), Division of Blood Applications, Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Kenneth C. Lowe (25), Department of Life Science, University of Nottingham – School of Biological Sciences, Nottingham, England, UK Eugene I. Maevsky (26), Thermodynamics and Energetics of Biological Systems, Institute of Theoretical and Experimental Biophysics of RAS, Pushkino, Moscow Region, Russia David H. Maillett (31), Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA Belur N. Manjula (39), Departments of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA Igor A. Maslennikov (26), The Scientific-Productive Company ‘Perftoran’, Pushchino, Moscow Region, Russia Barbara Matheson (42), Department of Biomedical Science, University of Maryland Dental School, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA Konrad Messmer (15, 16), Institute for Surgical Research, University of Munich, Munich, Germany Paula F. Moon-Massat (36, 37), Biopure Corpora- tion, Cambridge, MA, USA Ernest E. Moore (13), Denver Health, Denver, CO, USA Victor V. Moroz (26), The Research Institute of General Reanimatology, Petrovsky Bulv., Moscow, Russia Paulo Nascimento (12), Resuscitation Research Laboratory, Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA Deanna J. Nelson (34), BioLink Technologies, Inc., Cary, NC, USA John S. Olson (31), Rice University, Houston, TX, USA Joel Olsson (11), Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA List of Contributors x P759760-Prelims.qxd 9/14/05 10:31 AM Page x Thomas C. Page (6), Sangart Inc. Sorrento Valley, San Diego, CA, USA S. Scott Panter (21), Greenwich, San Francisco, CA, USA L. Bruce Pearce (36, 37), Biopure Corporation, Cambridge, MA, USA William T. Phillips (43), University of Texas Health Science Center at San Antonio, Department of Radiology, San Antonio, TX, USA Donald S. Prough (11), Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA Robert Przybelski (35), Department of Medicine, University of Wisconsin Medical School, Madison, WI, USA Sergey Yu. Pushkin (26), The Scientific-Productive Company ‘Perftoran’, Pushchino, Moscow Region, Russia Carl W. Rausch (37), Biopure Corporation, Cambridge, MA, USA Raymond F. Regan (21), Department of Emer- gency Medicine, Thomas Jefferson University, Philadelphia, PA, USA Virginia T. Rentko (36, 37), Biopure Corporation, Cambridge, MA, USA Thomas J. Richard (27), ChemVantage Consult- ants, LLC, St Louis, MO, USA Jean G. Riess (24), MRI Institute, University of California, San Diego, CA, USA Hiromi Sakai (44), Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Robert F. Shaw (27), University of California at San Francisco, HemaGen Corporation, CA, USA Toby Silverman (3), Division of Blood Applica- tions, Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Keitaro Sou (44), Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Donat R. Spahn (14), Service d’Anesthesiologie – CHUV, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Christer Svensén (11), Department of Anesthesiol- ogy, The University of Texas Medical Branch, Galveston, TX, USA Shinji Takeoka (44), Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Amy G.Tsai (7, 8), Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Eishun Tsuchida (44, 46), Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Sumreen U. Vaid (12), Resuscitation Research Laboratory, Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA Kim D. Vandegriff (5, 40), Sangart Inc., Sorrento Valley, San Diego, CA, USA Robert M. Winslow (1, 4,10, 30, 33, 40), Sangart Inc., and Department of Bioengineering, University of California, Sorrento Valley, San Diego, CA, USA J. Tze-Fe Wong (41), Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong Hisashi Yamamoto (46), Pharmaceutical Research Centre, NIPRO Corp., Kusatsu-shi, Shiga, Japan Mark Young (40), Sangart Inc., and Department of Bioengineering, University of California, Sorrento Valley, San Diego CA, USA List of Contributors xi P759760-Prelims.qxd 9/14/05 10:31 AM Page xi The precursor of this book was Hemoglobin- based Red Cell Substitutes, published by the Johns Hopkins Press in 1992 (Winslow, 1992). The initial idea for the current book was to pro- duce an updated edition, but somewhat less austere and more accessible to a wider reader- ship. As we worked on this idea it became less and less appealing, partly because the field has advanced so rapidly and so far since 1992. Furthermore, I became less and less confident that I would be able to do justice to the vast amount of new research that has been done since that time. Therefore it was decided that this book would be multi-authored. The book has several aims. First, it is intended to be comprehensive. Invitations to contribute were accepted by all but a few potential authors, and, except for a few hard cases, the authors have been extraordinarily prompt in accomplishing their contributions. Second, the book aims not to be a collection of disconnected essays, as so often happens in symposium proceedings; rather authors were asked to cover their field of specialization with background for the non- specialized reader before delving into the details of their own research. Third, the book aims for a degree of cohesiveness not usually found in multi-authored books. We have tried hard to ensure uniformity of usage and standardization of abbreviations. During the writing and editing stages, I frequently asked authors to resolve con- flicts with other chapters and to document state- ments that seemed to me to be matters of opinion. Fourth, we have tried to make the book accessible to the general reader. To do this, I have written a short abstract of each chapter; these abstracts are clearly identified as editor’s comments. Robert M. Winslow, MD San Diego REFERENCES Winslow, R. (1992). Hemoglobin-based Red Cell Substitutes. Baltimore: Johns Hopkins University Press. Preface P759760-Prelims.qxd 9/14/05 10:31 AM Page xiii I am very grateful to all the authors who have contributed to the book. All are experts in their own field, with serious demands on their time. Focusing on writing a chapter for a book like this is often an unwanted and unrewarded distraction. I hope the finished product is as useful to each of them as it has been exciting to me to edit. Margaret Macdonald and Victoria Lebedeva at Elsevier have been totally supportive at each stage of the project. I shall miss our monthly meetings in London with tea and scones. At Sangart, Pam Boltz has skillfully managed all of the daily chores of interacting with authors about details, prodding them to keep to deadlines and managing the pro- fusion of computer files that accumulate as revi- sions are collected. Robert M. Winslow, MD San Diego Acknowledgements P759760-Prelims.qxd 9/14/05 10:31 AM Page xv 2,3-DPG 2,3-diphosphoglycerate, an allosteric effector of hemoglobin O2 binding 2-IT 2-iminothiolane (Traut’s reagent) 3,4 DHBA 3,4 dihydroxybenzoate ��-Hb Hemoglobin crosslinked between � chains at Lys92 with bis-3,5(dibromo)salicylic acid (DBBF) AABB American Association of Blood Banks A-ANH Augmented acute normov- olemic hemodilution AAR Abdominal aortic reconstruction ABC America’s Blood Centers ABO Red blood cell surface antigens ADP Adenosine diphosphate AE Adverse event AHD Acute preoperative hemodilution AHSP Alpha hemoglobin stabilizing protein ALT Alanine aminotransferase ANH Acute normovolemic hemodilution aPTT Activated partial thromboplastin time AR Acetated Ringer’s solution USP ARC American Red Cross ARDS Acute respiratory distress syndrome AST Aspartate aminotransferase ATLS Advanced trauma life support ATP Adenosine triphosphate, the main substrate for energy metabolism AVM Arteriovenous malformations BAEC Bovine aortic endothelial cells BBB Blood – brain barrier BLA Biological license application BSE Bovine spongiform encephalitis BVDV Bovine diarrhea virus BvHb Bovine hemoglobin C(a – v)O2 Arterial – mixed venous O2 content difference C3 A component of complement C5a A component of complement CABG Coronary artery bypass graft cAMP Cyclic adenosine mono- phosphate CBER Center for Biologics Evaluation and Research (a component of the FDA) CCLI Chronic critical limb ischemia CHO Chinese hamster ovary cells CI Cardiac index (cardiac output divided by bodyweight) CJD Creutzfeldt – Jakob disease CK-MB Creatinine kinase, myocardial isoenzyme CNmetHb Cyanomet hemoglobin CNS Central nervous system CO Cardiac output COP Colloid osmotic pressure (oncotic pressure) CPB Cardiopulmonary bypass D5W 5% dextrose (glucose) in water, an intravenous solution Da Dalton, a unit of molecular weight DAB Diaminobenzoate DBBF bis-3,5(dibromo)salicylic acid, a hemoglobin crosslinker DBBF-Hb Same as ��-Hemaglobin DBBF-HvHb Bovine hemoglobin crosslinked with DBBF DCLHb Diaspirin crosslinked hemoglo- bin Baxter’s preparation of ��-Hb DCS Decompression sickness DECA Sebacyl crosslinked hemoglobin DHA Dehydroascorbic acid DHBA 2,3- and 2,5-dihydroxybenzoic acids DIC Disseminated intravascular coagulation Abbreviations P759760-Prelims.qxd 9/14/05 10:31 AM Page xvii DMC Degranulating mast cells DMF Drug master file DMPG Dimyristoyl-phosphatidyl glycerol DNA Deoxyribonucleic acid DO2 Oxygen delivery: cardiac output � arterial O2 content dP/dt The maximum positive slope of the arterial pressure curve DPPC Dipalmitoylphosphatidylcholine DPPG Dipalmitoyl-phospatidyl glycerol DSMB Data Safety Monitoring Board DSPC Distearoylphosphatidylcholine DxHb Dextran-linked hemoglobin EBL Estimated blood loss eBTr Embryonic bovine trachea cells EBV Exchangeable blood volume (also estimated blood volume) EC50 The effective concentration of a solution that kills 50 per cent of neurons in culture ECG Electrocardiogram ECMO Extracorporeal membrane oxygenation EDRF Endothelium derived relaxing factor EDTA Ethylene diamine tetraacetic acid Ees End systolic elasticity EMEA European Medicines Agency eNOS Endothelium-derived nitric oxide synthase EPO Erythropoietin EPR Electron paramagnetic resonance EVA Ethyl vinyl acetate EYP Egg-yolk phospholipid FCD Functional capillary density FDA US Food and Drug Administration FDMA Food and Drug Modernization Act FiO2 Fraction of inspired oxygen FOI Swedish Defense Establishment GCP Good clinical practices GFR Glomerular filtration rate GLP Good laboratory practices GMP Good manufacturing practices GPC Gel permeation chromatography GSH Glutathione H1S Hemopure 1 solution (Biopure) H1S-2 Similar to H1S but with reduced unpolymerized hemo- globin HAS Human serum albumin HAV Hepatitis A virus Hb Hemoglobin HbA Hemoglobin A, the main hemoglobin of the human red blood cell HbA0 HbA purified by chromatography HBOC Hemoglobin-based oxygen carrier HBOC-201 A formulation of glutaraldehyde-polymerized bovine hemoglobin produced by Biopure Corp. HBOC-301 A formulation of glutaralde- hyde-polymerized bovine hemoglobin produced by Biopure Corp. for veterinary use (Oxyglobin™) Hb-PEGP5K2 Hemoglobin modified by the attachment of two strands of PEG 5 kDa Hb-PEGP5K6 Hemoglobin conjugated to six strands of PEG 5000 kDa Hb-PEGP10K2 Hemoglobin modified by the attachment of 2 strands of PEG 10 kDa HbS Sickle cell hemoglobin HBV Hepatitis B virus Hct Hematocrit, the percentage volume of blood that is red blood cells HCV Hepatitis C virus HES Hydroxyethyl starch HIF Hypoxia inducible factor HIV Human immunodeficiency virus, the causative agent of AIDS HNLS Hyperinflated non-collapsible lung syndrome HO-1 Heme oxygenase 1 HO-2 Heme oxygenase 2 HO-3 Heme oxygenase 3 HS Hypertonic saline HSD Hypertonic saline dextran HSHb Hypertonic saline hemoglobin HSP70 Heat shock protein 70 Abbreviations xviii P759760-Prelims.qxd 9/14/05 10:31 AM Page xviii HTLV Human T lymphotropic cell virus HUVEC Human umbilical vein endothelial cells IAD Intraoperative autologous blood donation ICH Intracerebral hemorrhage ICP Intracranial pressure ICU Intensive care unit IHP Inositol hexaphosphate IL-5 Interleukin-5 IL-6 Interleukin 6, an inflammatory cytokine IND Investigational New Drug application to the FDA IRB Institutional Review Board ISS Injury severity score JCAHO Joint Commission for Accreditation of Healthcare Organizations kDa kiloDalton, 1000 Daltons LAD Left anterior descending coronary artery LAIR Letterman Army Institute of Research LDCR Late diastolic coronary resistance LDH Lactate dehydrogenase LEH Liposome-encapsulated hemo- globin L-NAME L-NG-nitro-arginine methyl ester LPS Lipopolysaccharide (endotoxin) LR Lactated Ringer’s solution USP MalPEG-Hb Hemoglobin modified by attachment of maleimide- activated PEG 5000 MAP Mean arterial pressure Mb Myoglobin MCA Middle cerebral artery MCP-1 Monocyte chemoattractant protein-1 MMS Monocyte-macrophage system (reticuloendothelial system) MOF Multiorgan failure MP4 MalPEG-Hb formulated at 4.2 g/dl in lactated Ringer’s solution MPAP Mean pulmonary artery pressure MRI Magnetic resonance imaging mRNA Messenger ribonucleic acid MVD Maximum valid dilution NADP Nicotinamide adenine dinu- cleotide phosphate NADPH Reduced form of NADP NAG N-acetyl-�-D-glucosaminidase NAT Nucleic acid amplification test NDA New Drug Application NEM N-ethyl maleimide NFPLP 2-Nor-2-formylpyridoxal 5�-phosphate NMR Nuclear magnetic resonance NO Nitric oxide NRC Neo red cells OEC Oxygen equilibrium curve OER Oxygen extraction ratio o-R-Poly-Hb Hemoglobin polymerized with o-Raffinose, a Hemosol product P50 The PO2 at which hemoglobin is half-saturated with oxygen PaCO2 PCO2 of arterial blood PAD Perioperative autologous donation of blood PaO2 PO2 of arterial blood PAOD Peripheral arterial occlusive disease PCO2 Partial pressure of CO2 PDH Hemoglobin permeability coefficient PEG Polyethylene glycol PEG-BvHb Bovine hemoglobin modified by surface conjugation to PEG PEG-Hb Bovine hemoglobin modified by surface conjugation to polyethylene glycol (PEG), a product of Enzon, Inc. PEG-PE Phosphatidylethanolamines PET Positron emission tomography PFC Perfluorocarbon PFD Perfluorodecalin PFMCP Perfluoro-N-4-(methylcyclo- hexyl)-piperidine PFOB Perfluorooctyl bromide (Perflubron) PFTMCH Perfluorotetramethylcyclohexane PFTPA Perfluorotripropylamine PGI2 Prostacyclin I2 PHP Pyridoxalated hemoglobin polyoxyethylene Abbreviations xix P759760-Prelims.qxd 9/14/05 10:31 AM Page xix