HEMOGLOBIN-BASED OXYGEN CARRIERS: A Long Road from Bench to Bedside

In Pediatric Hematology and Oncology Vol. 24, No. 4, Stefan, Uys, and Wessels [1], report on using a hemoglobin-based oxygen carrier (HBOC) as a bridge in a 2-year-old child with sickle cell disease, splenic sequestration, and severe anemia while waiting for her to recover from this complication of sickle cell disease. The therapy was successful and the child's life was surely saved by this intervention. There have been many antidotical reports of HBOCs being lifesaving in this hemoglobinopathy [[2], [3], [4], [5]]. Most report on the transfusion of patients who are Jehovah's Witness and have refused allogenic blood transfusion.

Blood transfusion is not without risk. Twenty years ago the risk of infection was extremely high and the prospect of a blood substitute seemed to hold promise for safe transfusions in the future. Blood transfusion continues to have risk, but the risk is reasonable for most of those patients who require it. The risk of infection is lower and may continue to decrease in the future. With the increase in blood safety the goal of HBOCs has changed from being a general substitute for allogenic blood transfusion to that of a “bridge” to allow oxygen delivery in situations where blood products are not immediately available to a time when they are, or decreasing the volume or need for allogenic transfusion during surgery. Considering the safety of blood products today, the efficacy of the HBOC must be equivalent to the transfusion of allogenic blood products or have some benefit that allogenic blood products do not have.

HBOCs include modified bovine or human hemoglobins, recombinant hemoglobin, or perfluorocarbons. Many of these HBOCs have been discontinued or are on research hold due to clinical problems with the product or inability to obtain Food and Drug Administration authorization to continue clinical trials of the product. Phase III trauma clinical trials focus on the hemoglobin-based oxygen carriers as a bridge to allogenic transfusion. Human trauma resuscitation research falls under the United States Code of Federal Regulations, Title 21, Exception From Informed Consent (21 CFR 50.24), as the patients are not able to consent at the time of need. This regulation requires that the current standard therapy is unproven or unsatisfactory and that the research therapy will have a direct benefit for the recipient. Phase III surgical trials usually use the avoidance or decrease of allogenic transfusion as a goal of the therapy and have to perform as well as allogenic blood products without increased morbidity.

A phase III trial in orthopedic surgical patients revealed that using a bovine hemoglobin HBOC led to a higher rate of morbidity [6] (serious adverse events, SAEs) overall, in particular, cardiac SAEs. A disproportionate number of the SAEs occurred in older patients. The most recent trauma trial using a human hemoglobin-based oxygen carrier could not prove that the HBOC was an improvement from standard resuscitation [7]. In this trial of prehospital administration of a hemoglobin-based oxygen carrier in trauma there was a high rate of protocol violations. This could reflect the fact that in the field it is difficult to follow complex protocols. Monitoring is not sophisticated, with the result that patients who might not benefit from a therapy will receive it by default. As an additional issue in trauma resuscitation, it is not always efficacious to increase volume and blood pressure [8] in a bleeding patient and both can occur when administering these products.

Even though advances in the development of hemoglobin-based oxygen carriers has made them much safer, they have not been shown to perform as well as allogenic transfusions and have toxicities that are not completely understood [9], such as vasoconstriction with resultant hypertension and resultant decreased circulation. Other morbidities have occurred during these large studies that indicate that HBOCs may not be as efficacious as allogenic transfusion or conventional therapy. The use of these products is as yet undefined by studies or practice. They may have a place in the emergent transfusion of those patients who have multiple alloantibodies, in patients who refuse allogenic blood transfusion, or in emergent situations were allogenic transfusion is not available for hours and exsanguination is eminent. New products are now in clinical trials and may perform better that these products, but not much has changed since Harvey Klein wrote an editorial following a similar anecdotal report 7 years ago [10], though we now have 2 phase III trials showing that HBOCs may not be an improvement over conventional therapy. This should not imply that there is no place for these products, only that it has been a very long and expensive road from the bench to clinical trials. Much has been learned and much has changed in transfusion medicine since the inception of these products, and their niche has become much smaller than previously thought.