Surgery News - April 2008 - (Page 19)

APRIL 2008 • SURGERY NEWS TRAUMA Blood Substitute Still Under Scrutiny B Y M I C H E L E G. S U L L I VA N Else vier Global Medical Ne ws N E W O R L E A N S — A blood substitute made of human hemoglobin extracted from expired donated blood can be used in emergencies when packed red cells are unavailable, according to recent phase III trial results. Survival rates of patients with traumatic injury who received the polymerized hemoglobin product (PolyHeme) before hospital transport were similar to those of patients who received crystalloid, and no increase in multisystem organ failure was seen, Dr. Ernest Moore said at the annual clinical congress of the American College of Surgeons. “PolyHeme is safe when used as an initial oxygen carrier. I’m not saying it should be used in lieu of packed red cells, but it can be used when that option is not available,” said Dr. Moore, an ACS Fellow who is vice-chairman of surgery at the University of Colorado Health Sciences Center, Denver, and was the trial’s principal investigator. Dr. Gary Vercruysse, who was asked to comment on the study, agreed. “What do you do with someone who is terribly injured and needs blood but you are not able to give it to them? Ideally, it would be nice to resuscitate people in the field without crystalloid, but that hasn’t been possible to this point. This trial showed that PolyHeme is not inferior to whole blood or crystalloid, and has the potential to show a survival benefit,” Dr. Vercruysse, a trauma surgeon at Grady Memorial Hospital, Atlanta, said in an interview. The study involved 32 U.S. institutions, 300 physician investigators, and 1,500 emergency medical technicians. Trauma patients who were at least 18 years old and had a systolic blood pressure of at least 90 mm Hg were eligible for inclusion. Patients who were considered unsalvageable or whose Glasgow Coma Scale grade was less than 5 were excluded. A total of 714 patients were enrolled in the trial, Dr. Moore said. Their mean age was 37 years, and most (78%) were male. Penetrating wounds were present in 53% of the patients; the rest had blunt injuries. Their mean systolic blood pressure was 78 mm Hg. Control patients (365) received crystalloid in the field, followed by packed red cells as necessary for the next 12 hours. PolyHeme patients (349) received the blood substitute in the field and, over the next 12 hours, up to six additional units as needed. Patients in both groups who needed additional transfusions after 12 hours received packed red cells. The 12-hour, in-hospital extension was added on the basis of a phase II trial showing that severely injured patients who got PolyHeme had lower rates of multiorgan failure than did those who received stored red blood cells. The main end points of the trial were 30-day mortality, multiple organ failure, and adverse events. Mortality was not significantly different between the control group and the PolyHeme group (10% versus 13%, respectively), nor was multiple organ failure (6% of controls versus 7% of PolyHeme patients). Significantly more PolyHeme patients than control patients had adverse events (93% versus 88%, respectively), but the difference for serious adverse events was not significant (40% of the PolyHeme group versus 35% of the controls). Similarly, significantly more myocardial infarctions occurred among PolyHeme patients than among controls (11 versus 3, or 3% versus 1%, respectively), but only one patient in each group required intervention, according to Dr. Moore. An independent group of cardiologists is reviewing these data as well as the cardiac profiles of all the patients in the trial, Dr. Moore said. Although the cause of the cardiac problems in the PolyHeme group is unclear, Dr. Vercruysse said that at no point during the trial was the independent safety monitoring board alarmed enough to intervene in the study. “This panel examined the safety data after 60, 120, 250, and 500 patients were accrued, and there was never any adjustment in the study or breaking of the blind to evaluate any safety imbalances.” Clinical trials of PolyHeme began in 1986. In 2006, a Wall Street Journal article raised public concern about the possibility of increased heart attacks in those who received the product, citing unpublished results of an earlier phase III trial of 152 patients in which MIs occurred in 10 PolyHeme recipients, 2 of whom died. None of those who received donated whole blood had an MI. That study examined the use of the blood substitute in elective surgery. “This was a trial of preoperative autologous blood donation, using PolyHeme to increase the red blood cell donation in patients undergoing elective abdominal aneurysm repair,” Dr. Moore said. “It was terminated at the first interim analysis because of a reportedly flawed study de- sign,” which led to PolyHeme patients having 60% of their blood volume withdrawn versus 30% in the control group. Northfield Labs Inc., the maker of PolyHeme, responded to the article in a news release on the company’s Web site: “In keeping with the protocol, the PolyHeme group also received substantially more fluids than did the controls, resulting in complex issues with fluid management in those patients.” The Wall Street Journal article insinuated that Northfield hastily stopped the trial and then buried news of the adverse events by refusing to publish the results. ‘I’M NOT SAYING IT SHOULD BE USED IN LIEU OF PACKED RED CELLS, BUT IT CAN BE USED WHEN THAT OPTION IS NOT AVAILABLE.’ According to Northfield’s press release, the trial closed in 2000 because of inadequate patient enrollment. Dr. Moore said that the data from this earlier phase III trial were fully reported to the Food and Drug Administration and formed the basis of several published reports. The 32 institutional boards of review that approved the trauma trial also had full access to the data, he added. But the newspaper article set off a chain reaction in the legal community, and five class action lawsuits were filed against Northfield. The current trial included patients who could not be identified prospectively, were in a life-threatening situation, and were unable to give fully informed consent to their randomization. Patient advocacy and community action groups protested, and ethicists published several opinion pieces, Dr. Vercruysse said. In an effort to reassure the communities involved in the trial, the study group sent out public notices to local media and community groups. Northfield also provided “opt-out” bracelets to community members who wished to be excluded from the trial in the event of an injury. “These ethical concerns were largely about the fact that patients continued to receive PolyHeme after ED admission for up to 12 hours, instead of blood, and without consent,” said Dr. Vercruysse. “Ethicists felt that once patients made it to the hospital, an attempt should have been made to contact families for consent before continuing to give PolyHeme over blood.” Indeed, Dr. James W. Jones, who was asked to comment on the study, found it “unconscionable” that this could have occurred. “It seems that the data [were] entirely controlled by the company and not the researchers. What blood bank would withdraw 60% of a patient’s blood volume? That would amount to six 500-mL units,” said Dr. Jones, an ACS Fellow with Baylor College of Medicine, Houston. The public discussion addressed the decision to randomize unknowing patients to whole blood transfusion or an unproven therapy. “By definition, [whole blood transfusion] is considered safe, but in this case it’s not as safe as it might seem. There are problems with whole blood that would never be an issue with PolyHeme: transfusion reactions, medical error in typing, transmission of viruses and bacteria, and priming for multiorgan failure,” Dr. Vercruysse said. But, he added, PolyHeme does seem to carry a small risk of increased cardiac problems. “I think we need to wait until the study is published before we form an opinion.” Northfield Labs Inc. sponsored the PolyHeme trial. Dr. Moore said he does not have any financial ties to the company or the product. http://www.facs.org/cancer/coc/comingtogether2008.html

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Surgery News - April 2008 Contents Comorbidities Sway Bariatric Outcomes Database Finds Gap in Dissection For Melanoma Future Surgeon Shortage Predicted Dexterity Demo Best for Bile? Health Policy Scan Plan

Surgery News - April 2008

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