Hemoglobin solutions come of age.

Hemoglobin Solutions Come of Age IN this issue of ANESTHESIOLOGY, Lamy et al. present their findings regarding the use of a commercially produced hemoglobin-based oxygen-carrying (HBOC) solution as an alternative to traditional allogeneic blood transfusions in patients who have undergone cardiac surgery. The study included a large number of patients (N 5 209) and involved the use of a commercially produced HBOC solution (Baxter, Deerfield, IL) in cardiac surgery patients after cardiopulmonary bypass. Although the study presents certain problems in study design, it is important because it illustrates the potential future importance of such HBOC materials, which are currently in clinical trials. The concept of using purified, chemically modified hemoglobin extracted from erythrocytes is not new and dates to the mid-19th century. In the approximately 100 yr that followed, numerous attempts have been made to develop HBOC solutions, largely in universityor hospital-based laboratories. In 1978, the promising clinical trial with such a material ended with significant systemic toxicity, leading workers in the field to conclude that hemoglobin itself is fundamentally toxic when outside of the erythrocyte. With the appearance of the human immunodeficiency virus infection in the early 1980s, allogeneic blood transfusions received increased scrutiny, and there appeared renewed interest in techniques to save allogeneic blood exposure. At that time, industry became involved in the development of HBOC solutions, and modern techniques of purification and process engineering were applied to this endeavor. The result was that by the late 1980s, hemoglobin solutions could be purified to the same degree and to the same standard that is applied to other high-volume parenteral solutions; the previously reported toxicities no longer occurred. Furthermore, advances in vascular biology and the opportunity to study these materials in numerous experimental systems has led to further understanding of their fundamental biologic properties. HBOC solutions have demonstrated potential for vascular reactivity, hypothesized to be the result of nitric oxide binding. Their ability to be transported in the plasma phase has important implications for their physiology in the microcirculation, and their degradation during elimination may liberate heme iron that may benefit postoperative hematopoiesis. With resolution of the previously observed toxicity problems, HBOC solutions have moved through phase I and phase II clinical trials and are entering final phase III clinical study for potential regulatory approval. As these materials have been put into clinical use, new issues have been identified and must be kept in mind. The present study by Lamy et al. further illustrates this point. With respect to study design, it is well recognized, particularly in cardiac surgery, that transfusion decisionmaking is a complex process that integrates measured physiologic parameters and a patient’s total hemoglobin level, as well as their age and cardiovascular reserve. In this particular clinical specialty, there is not a predetermined set of transfusion criteria; patient transfusion decisions are made by the bedside “integration” of the aforementioned parameters. Accordingly, designing clinical trials to assess the blood-conservation efficacy of HBOC solutions in cardiac surgery remains a challenge. Particularly because of this nature of transfusion criteria, the single-blind trial design in the study by Lamy et al. remains an important flaw that the authors have acknowledged. Nonetheless, this study did show bloodconservation efficacy when an HBOC solution was used in the immediate postoperative period after cardiac surgery. The amount of blood conservation was modest; however, the study used relatively low doses of HBOC solution. Further complicating the efficacy issue is the relatively short circulating half-life of these materials, complicated This Editorial View accompanies the following article: Lamy ML, Daily EK, Brichant J-F, Larbuisson RP, Demeyere RH, Vandermeersch EA, Lehot J-J, Parsloe MR, Berridge JC, Sinclair CJ, Baron J-F, Przybelski RJ, for the DCLHb Cardiac Surgery Trial Collaborative Group: Randomized trial of diaspirin crosslinked hemoglobin solution as an alternative to blood transfusion after cardiac surgery. ANESTHESIOLOGY 2000; 92:646–56. r