Blood substitutes: The future is now
Blood substitutes: The future is now
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DOI：
10.1016/s1072-7515(02)01704-0
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发表时间：
2003-01-01
影响因子：
5.2
通讯作者：
Moore, EE
中科院分区：
文献类型：
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作者：
Moore, EE
我感谢你们给我这个巨大的荣誉来做这个著名的演讲。正如我的前辈们雄辩地说过的那样，得到同行的认可是职业上最大的满足感。显然，站在这里的每个人都得到了那些更有能力、更明智的人的持久支持和建议。我对那些我永远感激不尽的人的清单是很丰富的。排在最前面的是约翰·H·戴维斯博士、本·艾斯曼博士、奥尔登·H·哈肯博士，尤其是我那极具耐心和洞察力的妻子萨拉·范·杜泽博士。我想花一点时间，代表广大的创伤社区，向C·詹姆斯·卡里科博士表示感谢，并铭记他不仅对创伤护理做出了巨大贡献，而且还体现了他作为慈爱的丈夫、慈爱的父亲、无私的学术领袖和无私的同事的理想。今天，我要克制住对美国医疗保健危机不断升级的悲叹，而是与你们分享我认为是我一生中最令人兴奋的研究进展之一，用于治疗受伤的病人。创伤外科医生，也许比任何其他卫生保健提供者更认识到血液替代品的巨大潜在临床效益（表1）。无论是地方性的（丹佛高中大屠杀），全国性的（纽约和五角大楼发生的9/11悲剧），还是国际性的（正在进行的反恐战争），我们都迫切需要开发这种维持生命的资源。我相信这种临床益处最终实现的那一天已经到来，因此，我选择在本次论坛上回顾血液代用品在创伤护理中的科学背景、现状和未来应用。这将是一个有偏见的观点，因为它主要是基于我在过去十年中与Steven a Gould， MD和Northfield Laboratories， Inc （Evanston， IL）密切合作的机会，在他们的人聚合血红蛋白（Hb）溶液PolyHeme中，对受伤患者的护理。目前正在接受美国食品和药物管理局（FDA） III期临床试验的血液替代品是红细胞（RBC）替代品，从根本上提供血红蛋白的呼吸功能。已经开发出替代血小板7、血小板8和血浆凝血因子的药物；它们与一种红细胞替代品的结合将是未来治疗晚期失血性休克的一种受欢迎的改进方法。目前最有前途的红细胞替代品包括从裂解的红细胞中提取的血红蛋白，通常被称为血红蛋白基氧载体（HBOCs）。血红蛋白生理学（图1）血红蛋白被认为是氧气（O2）运输所必需的。11成人Hb由两条和两条多肽链组成，每条多肽链都与一个能够结合一个O2分子的血红素基团结合（1g Hb结合1.39 mL O2）。Hb四聚体的分子量为64,500。脱氧血红蛋白的珠蛋白亚基在静电力作用下保持紧绷的构象，对氧的亲和力相对较低。当O2与血红素结合时，机械化学应力削弱了静电力，导致松弛构象；这暴露了剩余的结合位点，并将O2亲和力提高了500倍。Hill系数反映了Hb上多个O2结合位点的协同作用，导致血红蛋白氧解离曲线呈s形。成人红细胞的希尔系数为2.7（范围为2.4 ~ 2.9）。改变o2结合亲和力的因素包括红细胞2,3 -二磷酸甘油酸（2,3 - dpg）含量、血液中二氧化碳和氢离子浓度以及体温。绑定2,3…
I thank you for the tremendous honor of presenting this prestigious lecture. As eloquently stated by those preceding me, there is no greater professional satisfaction than to be recognized by your peers. Clearly no one stands here without the enduring support and counsel of those more capable and wise. My inventory of those to whom I am forever indebted is extensive. At the top of the list are Dr John H Davis, Dr Ben Eiseman, Dr Alden H Harken, and especially my incredibly patient and insightful spouse, Dr Sarah Van Duzer. I would like to take a moment, on behalf of the extended trauma community, to express gratitude to and remember Dr C James Carrico not only for his enormous contributions to trauma care but also for the ideals he exemplified as a loving husband, caring father, altruistic academic leader, and unselfish colleague. Today I am going to resist the overwhelming desire to lament the escalating crisis in US health care, but rather share with you what I believe is one of the most exciting research developments in my lifetime for care of the injured patient. Trauma surgeons, perhaps more than any other health care providers, recognize the tremendous potential clinical benefit of a blood substitute (Table 1). Whether locally—the high school massacre in Denver, 1 nationally—the tragic 9/11 events in New York City and the Pentagon, 2 or internationally—the ongoing war against terrorism, 3 there is a sense of urgency to develop this life-sustaining resource. I believe the day this clinical benefit will finally be realized has arrived and, consequently, have chosen to review at this forum the scientific background, current status, and future application of blood substitutes in trauma care. This will be a biased perspective, because it is based principally on my opportunity to work closely with Steven A Gould, MD and Northfield Laboratories, Inc (Evanston, IL), in the insinuation of their human polymerized hemoglobin (Hb) solution, PolyHeme, into the care of the injured patient over the past decade. 4-6 The current generation of blood substitutes undergoing US Food and Drug Administration (FDA) phase III clinical testing are red blood cell (RBC) substitutes and fundamentally provide the respiratory function of hemoglobin. Agents have been developed to replace platelets 7, 8 and plasma coagulation factors; 9, 10 their combination with an RBC substitute will be a welcome refinement for the treatment of advanced hemorrhagic shock in the future. The most promising RBC substitutes at this time consist of extracted Hb from lysed RBCs, often referred to as hemoglobin-based oxygen carriers (HBOCs).Hemoglobin physiology (Fig. 1) Hemoglobin is recognized as essential for the transport of oxygen (O2). 11 Adult human Hb consists of twoand two polypeptide chains, each bound to a heme group capable of binding one molecule of O2 (1 g of Hb binds 1.39 mL of O2). The molecular weight of the Hb tetramer is 64,500. The globin subunits of deoxyhemoglobin are held by electrostatic forces in a tense conformation with a relatively low affinity for O2. When O2 binds to a heme group, mechanochemical stresses weaken the electrostatic forces, resulting in a relaxed conformation; this exposes remaining binding sites and increases O2 affinity 500-fold. The Hill coefficient reflects the cooperative effect of multiple O2 binding sites on Hb, responsible for the sigmoid shape of the oxyhemoglobin dissociation curve. The Hill coefficient of the adult RBC is 2.7 (range 2.4 to 2.9). Factors that modify O2-binding affinity include RBC 2, 3-diphosphoglycerate (2, 3-DPG) content, the concentration of carbon dioxide and hydrogen ion in blood, and body temperature. Binding of 2, 3 …