Polyheme is a hemoglobin based oxygen carrier and, as the only blood substitute to reach a Phase III trial, represents the leading technology in this field. Developed and manufactured by Chicago based Northfield Laboratories, Inc., Polyheme originally began as a military project following the Vietnam War and has since shown great potential for both military and civilian use.
Polyheme utilizes human hemoglobin as the oxygen carrying molecule in solution, and the extraction and filtration of this hemoglobin from red blood cells is the first step in production. Then, using a multi-step polymerization process illustrated below, the purified hemoglobin is associated into tetramers and, as the final step, is incorporated into an electrolyte solution.
The polymerization of the hemoglobin represents the critical step in this process because, as demonstrated by failed attempts at blood substitutes, when hemoglobin remains disassociated, it tends to take up nitric oxide, causing vasoconstriction. Also, free hemoglobin can be taken up by the kidney causing liver dysfunction and failure.
Artificial blood substitutes in general have inherent advantages over the donor system in place today. However, a blood substitute has yet to be developed that can effectively and safely mimic all the functions of natural blood. Polyheme has come the furthest of all blood substitutes currently in trials, and if approved for general use, has great life-saving potential.
1. Donor blood is often in short supply and expires after only 42 days. Polyheme has the possibility to be manufactured to stock hospitals across the country, so that the supply is never limited, and carries a shelf life of 12 months.
2. When natural blood is available for transfusion, both the donor blood and the recipient blood must be carefully matched, a process that in the best facilities takes 20 minutes but can take up to an hour. Polyheme is universally compatible, meaning any blood type can accept it, and can be transfused immediately. That time difference can easily save the lives of severely hemorrhaging patients who otherwise would have died. Also, since Polyheme is thinner than normal blood, it can be transfused more rapidly and can safely be transfused in large volumes.
3. Polyheme is manufactured in such a way so as to bring the risk of disease transmission to virtually zero. While the risk of contracting disease from donated blood has been decreasing with improved tests, there is still a chance. Certain tests done on donated blood only indicate the presence of antibodies to a particular antigen. These antibodies, depending on the phase of the disease, may not yet be completely formed during the period when the blood is donated and then transfused. Also, new pathogens such as prions, which are responsible for bovine spongiform encephalitis, or mad cow disease, are not yet able to be detected in blood. Polyheme completely circumvents these risks.
Polyheme was developed just as a temporary solution to blood loss. As a military project, the focus was to develop a blood substitute to keep trauma patients alive in remote areas where donated blood is not available, until they can reach more sophisticated facilities. While it can effectively replace blood function, Polyheme cannot necessarily do it for extended periods of time, having a circulation half-life of only 24 hours. Conditions requiring blood for longer than the circulation time of Polyheme would require repeated transfusions of Polyheme or later replacement with donor blood. While this product, given this condition, still carries enormous life-saving potential, the short circulation time is still a problem, or at least something to be improved upon.
Another factor that can limit the effectiveness of Polyheme is the fact that it is manufactured using human hemoglobin. While this hemoglobin can be reclaimed from expired red blood cell products, it does not completely eliminate the need for donors because there must be a source of the outdated erythrocytes. The use of human hemoglobin could limit the supply and manufacturing potential of Polyheme, and while it has a shelf life much longer than donated blood, it will also be used more quickly due to the short circulation time. All this adds up to a limit on the supply of Polyheme.
Multiple clinical trials have already been completed in the hospital setting which increasingly test the safety and effectiveness of Polyheme. Testing has included transfusion of Polyheme during resuscitation as well as both intraoperatively and postoperatively, and has shown the effectiveness of Polyheme at different rates, from 1 unit to 20 units. The most rapid transfusion occurred during a severe hemorrhage when 20 units were transfused in 20 minutes during a Phase II clinical trial. In all cases of randomized trials, patients receiving Polyheme showed increased survival over those not receiving blood.
Perhaps the most telling trial to date, however, was one done out of necessity. In a nonrandomized trauma trial in a hospital setting in 2001, Polyheme was administered to 171 patients when donor blood was unavailable to replace blood lost from trauma or during surgery. Some patients were kept alive as they lost all their blood and received repeated transfusions of Polyheme to compensate for the ongoing bleeding. The findings from this study were were presented at the Clinical Congress of the American College of Surgeons, in October 2001, and later published in the October 2002 issue of the Journal of the American College of Surgery.
Polyheme is currently undergoing a Phase III clinical trial, which is the first trial in the United States of a hemoglobin based oxygen carrier in the prehospital setting, and is meant to determine the safety and efficacy of the blood substitute. Northfield Laboratories, Inc., which now operates the study in 28 level 1 trauma centers throughout the country, hopes to include 720 random patients over the one year trial period. During the study, Polyheme is deployed in ambulances to patients who are suffering from hemorrhagic shock, such as victims of car accidents or violence. If the patient qualifies for the study, he is then either randomly placed into the control group or the trial group. The control group receives the standard of care, namely saline solution during the ambulance ride for hydration and then donor blood transfusion upon arrival at the hospital if necessary, and his progress is monitored for comparison. The trial group receives Polyheme treatment immediately upon the ambulance arriving on the scene and continued treatment in transport and at the hospital for up to 12 hours or 6 units of Polyheme, after which time donor blood will be used if necessary.
In order to qualify for the study, the patient must be an adult following trauma who has sustained blood loss and is in shock. However, anyone who is pregnant, has suffered head or potentially fatal injuries, has gone into cardiac arrest, or objects to the study based on religious or other grounds is disqualified.
This Phase III study has caused controversy among bioethicists, however, due to the fact that those participating in the study never give consent. Northfield Laboratories, Inc., states that due to the nature of the injuries being treated, the patients are unable to give consent and the study is therefore being conducted under a special section under the Code of Federal Regulations. Section 50.24 allows for the exception of informed consent under circumstances of emergency research when the medical condition of the patient requires immediate care, available treatments are unsatisfactory, previous studies demonstrate the potential to provide a direct benefit to the patient, and the risks are reasonable given what is known of the patients’ medical condition. Opponents of this study point to the fact that patients never get a chance to refuse the experimental blood substitute as automatic grounds for its discontinuation. Also, this provision for emergency research without informed consent, which was passed in 1996, was used as means to launch a Baxter Healthcare study in 1998. The study, which was the first major study of artificial blood, was cut short with disastrous results as almost half of the 52 patients died. In order to avoid criticism, the hospitals conducting this study have mandatory community meetings to educate the residents about the trial. Despite the fact that most residents do not object to the study, only one in 57 objected at the Loyola University Medical Center in Illinois, some medical centers have devised ways to allow residents to opt out if they want. For instance, at the Denver Health Medical Center, people who object for religious or other reasons can wear a bracelet that indicates their preference. This method has come under scrutiny, however, with many ethicists, most significantly Vera Hassner Sharav, president and founder of the New York-based Alliance for Human Research Protection, claiming that the burden should not be placed on those who do not wish to participate in the study, but rather on those who will. While the bioethics community remains divided on the issue, the Food and Drug Administration stands by their decision to allow the Phase III trial.
Nothfield Laboratories has also come under criticism for targeting minority and low income neighborhoods for the study. For instance, in San Diego, only ambulances working south of Interstate 8, a traditionally bad neighborhood, were equipped with Polyheme. Devon Price, the company’s spokesman, claimed that the company wanted to perform the study in neighborhoods with high rates of traumatic episodes. Opponents, however, point to the fact that in many neighborhoods with the study, ads were supposed to be posted in newspapers and on television indicating the nature of the study and ways to opt out, but never were. The only notice in San Diego was an obscure link on a UCSD website. Human rights activists also say that by performing the study in low income neighborhoods, the company is trying to protect itself because if anything does go wrong, the residents are not in a position financially to sue for damages.
In addition to patients’ rights problems, Northfield Laboratories has had to deal with some disturbing results as of late. In May 2005, researchers at Walter Reed Army Institute of Research performed an experiment comparing the safety and efficacy of resuscitative fluids in treating hemorrhaging lab rats. The results indicated that Polyheme may not be as safe as previously thought, with the data indicating that rats being treated with PolyHeme experienced higher mortality rates than those that received two commonly used solutions.