Although other HBOCs have been studied in clinical trials, the results have been under-reported to date. These products include Hemosol's Hemolink and Somatogen's Optro. Development of both products was reportedly halted due to increased rates of cardiac arrest. Both companies have ceased operations.
In the following sections, we review the research and development process and results from the key clinical trials of HemAssist, PolyHeme, and Hemopure.
Additionally, we also reviewed company press releases to find information regarding recent trials and company efforts. We omitted Phase I clinical trials in healthy volunteers, case reports, trials with no control group, trials with fewer than 40 participants, and interim studies that were subsequently published in full. We extracted data regarding patient populations, HBOC dosage, the control group dosage and key results for all included studies.
These scientists eventually created diaspirin cross-linked hemoglobin DCHb. In order to move their product to the larger scale for clinical trial lots, competitive bids were solicited from private industry and DCLHb was eventually licensed to Baxter Healthcare in The source of hemoglobin was outdated human red blood cells that were pooled, washed, lysed and filtered.
The product was then deoxygenated, crosslinked with bis 3,5-dibromosalicyl fumarate, and reoxygenated. Table 1 lists additional characteristics of DCLHb. Conflicts arose between the LAIR group and Baxter over direction of research and development and the two groups severed ties. Baxter Healthcare continued to develop the product, which they called HemAssist, and aggressively pursued animal studies and clinical trials. The U. Overall, the results of the U. Army's sponsored research were discouraging, while Baxter's animal research suggested that HemAssist might have clinical efficiency.
No published study documented a difference between the U. Baxter performed over a hundred animal studies and the U. Army published several studies, with some reports indicating that the product caused vasoconstriction.
Army sponsored studies that suggested the vasoconstriction was a severe limitation, but the Baxter studies found that HemAssist improved tissue oxygenation and hypothesized that clinical benefits might result from the vasoconstriction. Army funded initial studies and the company went public in In contrast with Baxter, Northfield published little data from animal studies and performed only a few clinical trials.
However, on closer examination of the references, only five studies presented clinical data. These studies provided sparse data regarding the physiological occurrences during infusion, but focused instead on reductions in the requirement for red blood cell RBC transfusions as a result of product usage.
The only published animal studies on PolyHeme that included significant physiologic data were performed recently in independent experimental assessments of PolyHeme performed by the U. The physiological effects of PolyHeme were largely unknown to the research community until these recent studies. Northfield reported that PolyHeme was devoid of the vasoconstrictive effects that was a noted side effect of the other HBOCs. Northfield's clinical studies revealed only mild increases in systemic blood pressure, but did not include acute data on cardiac output, pulmonary pressures, calculated vascular resistances.
Studies performed in independent U. Army laboratories demonstrated that PolyHeme exhibited vasoconstrictive properties and conferred no survival value in swine and rat models of hemorrhage. SFH-P is produced by crosslinking the stroma-free hemoglobin from outdated RBCs with glutaraldehyde and then pyridoxylating it. To obtain a COP that is near the normal value, the hemoglobin is polymerized with glutaraldehyde and all unreacted tetramer is then removed.
The viscosity is double that of saline. Northfield completed enrollment for PolyHeme's Phase III trials in July and reported results from those trials in late and mid HBOC is Hemopure's third-generation product; the company had previously developed two other solutions that were explored through various pharmacological studies.
Its properties are similar to those of HBOC, with a lower average molecular weight. Oxyglobin continues to receive significant enthusiasm from many veterinarians. HBOC is Hemopure's current product for human use and has undergone both animal studies and extensive clinical testing. HBOC is derived from bovine hemoglobin, polymerized with glutaraldehyde. The solution is ultrapurified, which removes or inactivates potential contaminants such as cellular stroma, infectious agents and endotoxins.
HBOC's P 50 is 40 mmHg, resulting in a lower oxygen affinity than native hemoglobin and the lowest P 50 of the three solutions. Additionally it exhibits the highest methemoglobin percentage and the heaviest average weight of the three products. It also has the longest shelf life and can be stored at the widest range of temperatures. Several smaller trials are not listed or discussed because they are either interim studies or have a very small patient population.
We list the primary conclusions from the published studies and we only report physiologic effects that were statistically significant. We report all results on blood sparing and any other major clinical finding as reported by the authors, regardless of their statistical significance. The key clinical trials that evaluated HemAssist are listed in Table 2.
The HemAssist group exhibited increased systemic and pulmonary vascular resistances and pressures compared with the control group. Mortality was similar in both groups. Although patients in the HemAssist group received significantly less PRBC units on day 0 and day 1 post surgery, a significant reduction in the total number of PRBCs administered was not observed because the HemAssist patients did not cumulatively receive less blood products over the course of the study.
A study of 85 patients who had experienced acute ischemic stroke evaluated the use of HemAssist within 18 hours of the onset of symptoms. Normal saline was used as the control. The patients were evaluated at three months. Severe stroke at baseline and treatment with DCLHb showed to be independent predictors of an unfavorable outcome, based upon the Rankin scale.
However, the HemAssist-treated patients were also more likely to suffer from adverse effects. Because of safety concerns, the study was terminated early. In , Baxter launched their final, pivotal study, testing HemAssist on patients in ambulance and emergency departments ED in both the United States and Europe.
For the U. Patients were to receive either mL of HemAssist or normal saline. The cause for the increased mortality could not be established from that data. However, researchers speculated that it was a result of the known vasopressor effects of hemoglobin solutions.
Baxter had also initiated a separate study in Europe around that time. A study involving patients suffering from severe hemorrhagic shock examined the use of HemAssist in reducing MOF from tissue hypoxia. However, the study was prematurely terminated because HemAssist did not significantly reduce rates of organ failure and because researchers could not offset other concerns raised about HemAssist's safety record during the U. Because of these problems, commercial production of HemAssist ceased.
Baxter evaluated recombinant hemoglobin formulations for a several more years and eventually terminated its HBOC program. Adverse events or safety issues were not reported for PolyHeme, suggesting it was well-tolerated in this setting. PolyHeme maintained hemoglobin concentration and reduced the need for allogeneic blood by approximately 3. Another large study compared trauma patients who received PolyHeme during surgery to a historical control group of patients who refused red cells for religious reasons.
However, the U. In December , Northfield announced in a press release it had completed enrollment in its Phase III clinical trial. At the same time, the company released preliminary data. Thirty-one An early clinical study with Hemopure patients undergoing elective abdominal surgery illustrated a key physiologic function of HBOCs. Because of the reported increase in mean arterial pressure and systemic vascular resistance, as well as the notable decrease in cardiac index, the authors concluded that Hemopure impaired oxygen delivery because it induced a reduction in cardiac output.
Similar results impaired cardiac output despite the expected volume expansion have also been reported for HemAssist and PolyHeme. Another intraoperative study evaluated 72 patients undergoing infrarenal aortic reconstruction, randomized in a 2 to 1 ratio to receive either Hemopure or red blood cell transfusions.
A randomized, double-blind trial of Hemopure evaluated its efficacy as an alternative to red blood cell transfusion. The Hemopure patients received 60 g of Hemopure in mL for the initial transfusion and up to two additional infusions of 30 g in mL over the next 72 hours. In a randomized, single-blinded trial, the tolerability of a single dose of Hemopure was evaluated. After evaluating Hemopure's effects on blood chemistry, hemoglobin concentration, methemoglobin concentration, urine output and pressure, the authors concluded that Hemopure was generally well-tolerated.
However patients' blood pressures were slightly, but consistently, higher in the Hemopure group. In December , the FDA denied Biopure's application to study Hemopure in a Phase III trauma trial and recommended it undergo a pre-hospital Phase II study to evaluate its safety and efficacy in a study with a smaller patient population.
The Hemopure patients received up to g of Hemopure in 2, mL over a maximum of six days. Any additional blood requirements were met with PRBCs. The control group was administered PRBCs as needed. However, the rate of adverse effects in the Hemopure group was significantly higher. Perhaps because of the ambiguous results that resulted from the perioperative and ICU trials, all three companies elected to perform their Phase III trials in the pre-hospital trauma setting. They chose to do this because blood is not available during the pre-hospital period and therefore the investigators thought the rapid delivery of HBOCs may have the greatest impact on survival in this setting.
The rationale for the setting was the potential that these HBOCs could potentially save more lives than were lost in the emergent trauma setting and that they could significantly reduce the number of transfusions required by patients. The FDA considers non-inferiority trials to be an acceptable study design and an acceptable marketing base for companies.
Last Update Posted : October 4, Study Description. The purpose of this protocol is to provide treatment with HBOC to patients with life-threatening anemia for whom allogeneic blood transfusion is not an option. HBOC [hemoglobin glutamer - bovine ] has been previously studied as an alternative to blood transfusions in severely anemic patients needing a way to enhance tissue oxygenation.
HBOC is purified, cross-linked and polymerized acellular bovine hemoglobin in a modified lactated Ringer's solution, and does not require blood compatibility. FDA Resources. Intervention Details: Biological: HBOC Intravenous administration of a hemoglobin based oxygen carrier HBOC in patients with life-threatening anemia, for whom allogeneic blood transfusion is not an option. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.
Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. More Information. Risk-adjusted clinical outcomes in patients enrolled in a bloodless program. Epub Jun The need for additional dose administration should be assessed after each infusion as clinically indicated.
Dosing will be stopped if any one of the following occurs:. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information. Search for terms. Save this study. Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U.
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