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Thread: Results of Blood Substitute Trial Show No Survival Advantage to Trauma Patients

  1. #1

    Smile Results of Blood Substitute Trial Show No Survival Advantage to Trauma Patients

    Here is an interesting article published today (10-26-2007) by DukeMedNews.org:

    Here is the link to the article: || DukeMedNews || Results of Blood Substitute Trial Show No Survival Advantage to Trauma Patients

    date : 10/25/2007
    media contact : Richard Merritt , (919) 684-4148
    merri006@mc.duke.edu

    DURHAM, N.C. The results of a large multi-center research trial of a blood substitute for patients with life-threatening trauma and blood loss show no difference in survival between patients receiving the blood substitute, PolyHeme, in the first 12 hours after injury and those receiving the current standard of care, which is saline (salt water) prior to arrival at the hospital and saline plus blood transfusions, if needed, after arrival to the hospital. Duke University Medical Center was one of 32 sites in 19 states participating in the research trial.

    Because the patients who could be in the study were unlikely to be able to provide informed consent due to the nature and seriousness of their injuries, the study was conducted under FDA regulations that allow for clinical research in emergency settings using an exception from the requirement for informed consent. Before beginning the trial, each center conducted a series of information sessions and other educational efforts throughout the community describing the details of the trial. Residents who did not want to participate in the research study were instructed to notify the study site to "opt out."

    Nationwide, a total of 714 patients were enrolled in the trial 350 were randomized to receive PolyHeme and 364 were randomized to the standard of care group. The trial was intended to determine whether or not PolyHeme was better than the traditional treatment.

    According to Northfield Laboratories, the Evanston, Ill.-based company that developed PolyHeme, 13 percent of the patients who received PolyHeme died, while 10 percent of the control group died. The difference in the number of deaths between the two groups was not statistically significant, meaning the outcomes were similar regardless of the treatment the patient received, the company reported. Full study results have not yet been published in an independent medical journal.

    At Duke, a total of seven patients were enrolled in the trial four were randomized to the PolyHeme group and three to the control group. All seven patients survived without experiencing serious adverse side effects and were discharged from the hospital, according to Steven Vaslef, M.D., director of the Duke Trauma Center and Duke's principal investigator for the trial.

    The results of the trial were first reported at 93rd annual meeting of the American College of Surgeons on Oct. 10.

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  3. #2
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    Which is more expensive?

    Is the polyheme cheaper than the current SOC?

  4. #3
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    Polyheme is not marketed yet, however, we can safely assume that it will be many times more expensive.
    Jim Laws

  5. #4
    Managing Editor Jan B. Wade's Avatar
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    Money Matters

    Polyheme or any other "blood substitute" (actually oxygen carrier) will be very expensive until a generic is available. Recombinant EPO made Amgen and Ortho Biotech rich. Now Amgen fights companies who are trying to develop a similar product. They are fighting to protect their profits.
    Mr. Jan B. Wade
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  6. #5
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    Perhaps someone can help me with a definition of "oxygen carrier"? It seems to be a hemoglobin derivative or fraction, is this correct? Any help would be appreciated. Thanks!

  7. #6
    Managing Editor Jan B. Wade's Avatar
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    modified hemoglobin

    http://www.noblood.org/wiki/Polyheme

    There are two basic groups of synthetic oxygen carriers. One is based on perflourorcarbons the other on modified hemoglobin.

    You are asking about modified hemoglobin. Here's an in depth discussion however the answer to your question are is in section 2.

    MODIFIED HEMOGLOBIN

    1. General:
    Research on modified hemoglobin was initiated by the author since 1957 (Chang 1957, 1964, 1965, 1966). However, concentrated research and development on modified hemoglobin only started after 1987 because of public concerns of AIDS from donor blood. Modified hemoglobin can be sterilized to remove microorganisms including those responsible for AIDS, Hepatitis and others. In addition, there are many situations where modified hemoglobin can be used to substitute red blood cells (5). This includes many types of major surgery where a large amount of blood is needed. It is also particularly useful in severe traumatic injuries in traffic accidents and other accidents that result in severe bleeding. The number for this could be very large in major disasters like earthquakes or wars
    (6) . Modified hemoglobin is especially useful in these emergency situations. Modified hemoglobin does not contain blood group antigens, therefore it can be used without the need for crossmatching or typing. This would saves much time and facilities and would permit on the spot transfusion as required, similar to giving intravenous salt solution. Furthermore, modified hemoglobin can be lyophilized and stored as a stable dried powder which can be reconstituted with the appropriate salt solution just before use.


    2. What are modified hemoglobin ?
    Hemoglobin molecules extracted from red blood cells are modified by microencapsulation or crosslinkage. This stabilizes the hemoglobin molecules and also allows the sterilization of the products to remove H.I.V. and other microorganisms. Rapid progress has been made in the last 7 years towards clinical use. A number of companies working in this area are now carrying out clinical trials in human. Some have progress to different stages of Phase III clinical trial (see clinical trial). The following is a more detailed description.


    3. Why do we have to modify hemoglobin ?
    Hemoglobin is the oxygen carrying protein of red blood cells. Hemoglobin molecules inside red blood cells are in the form of a tetramers (Fig. 1). Red blood cell membrane retains the cofactor 2,3-DPG which is needed by hemoglobin for it to readily release oxygen as required - high P50. Hemoglobin can be extracted from red blood cells by removing the cell membranes to form stroma-free hemoglobin(7). However, this cannot be used as blood substitutes. When infused into the circulation each hemoglobin molecule of 4 subunits (tetramer) is rapidly broken down into 2 subunits (dimers) (Fig. 2). The smaller dimers are rapidly excreted by the kidneys. This also has renal toxicity. Furthermore, without the required cofactor (2,3-DPG) when outside the red blood cells, hemoglobin cannot readily release oxygen as required (Fig. 2). Two biotechnological approaches are used to modify hemoglobin to prevent these problems.


    4. Encapsulated hemoglobin: artificial red blood cells.
    The author first reported the preparation of artificial red blood cells(Chang 1957, 1964)(Fig.3). These have P50 and oxygen dissociation curve similar to red blood cells, since 2-3-DPG is reatainedn inside (1)(Fig.3). Hemoglobin also stays inside as tetramers (Fig 3). These artificial red blood cells do not have blood group antigens on the membrane and therefore do no aggregation in the presence of blood group antibodies (4). However, the single major problem is the rapid removal of these artificial cells from the circulation. Much of the studies since that time are to improve survival in the circulation by decreasing uptake by the reticuloendothelial system. Preparation of smaller submicron lipid membrane artificial red blood cells resulted in improvements in circulation time(12). Microencapsulated hemoglobin or artificial red blood cells are now being extensively explored by many researchers around the world. These recent advances make possible the following results. The average half-time in the circulation is now up to 20 hours. The uptake is mainly by the reticuloendothelial system. It is possible to replace 90% of the red blood cells in rats with these artificial red blood cells. The animals with this percentage of exchange transfusion still remain viable. Studies also reported effectiveness in hemorrhagic shock. Preliminary study by a number of groups shows that they are not toxic. There are no changes in the histology of brain, heart, kidneys and lungs of rats. To further improve stability and biodegradability, we are now using biodegradable polymer membrane to prepare artificial red blood cells of less than 200 nanometre (less than 0.2 micron) diameter (16).


    Microencapsulation of hemoglobin to prepare artificial red blood cell is a rather ambitious approach (1). Although this attempt to mimic red blood cells has resulted in a complete red blood cell substitute, it is rather complicated. Further research is needed and this approach is now considered as a second generation modified hemoglobin. A simpler crosslinked modified hemoglobin has been developed as a first generation modified hemoglobin for more immediate clinical applications.


    5. Crosslinked hemolgobin
    (i) Polyhemoglobin: Hemoglobin contains many amino groups most of which are on the surface of the hemoglobin molecule. The author first reported the use of a bifunctional agent (diacid) to crosslink hemoglobin (Chang 1964,1965). This was used first to form cross-linked hemoglobin membranes for artificial red blood cells, but it was found that with decreasing size of artificial cells all the hemoglobin molecules are crosslinked into polyhemoglobin (Chang 1964,1965). The reaction is as followed:

    Cl-CO-(CH2)8-CO-Cl + HB-NH2 = HB-NH-CO-(CH2)8-CO-NH-HB Diacid
    Hemoglobin Crosslinked hemoglobin (Chang 1964)

    Extensive studies have been carried out by many groups especially in the last 7 years on crosslinked hemoglobin.(8-11)(Fig.4). Crosslinking prevents the breakdown of hemoglobin tetramers into dimers (2,3). Smaller polyhemoglobin consisting of 4 to 5 hemoglobin molecules stays longer in the circulation . The addition of a 2,3-DPG analogue, pyridoxal phosphate, to crosslinked hemoglobin improves the P50 (18). This approach have been developed (19-22) so that it is the first crosslinked hemoglobin used in clinical trial (22). Phase III clinical trials by the Northfield group
    (Update: Phase III completed and filed for F.D.A. approval) and the Biopure group (Update: Approved for routine use in patients in South Africa) show that up to 10,000ml can be infused with no reported adverse effect. It also replaces the lost red blood cells. The crosslinking reaction used by these two groups is based on a bifunctional crosslinking agent, glutaraldehyde (Chang 1971), very similar to the crosslinkage reported earlier (Chang 1964, 1965) in the above equation:

    H-CO-(CH2)3-CO-H + HB-NH2 = HB-NH-CO-(CH2)3-CO-NH-HB glutaraldehyde
    hemoglobin Crosslinked Hemoglobin (Chang 1971)

    At present, other crosslinkers are also being developed (Table I). These are designed to have the dual function of a bifunctional crosslinker which also acts as a 2,3-DPG analogue. Some of these are based on bifunctional dialdehydes derived from oxidizing the ring structures of sugars or nucleotides.One approach in clinical trial involves the use of a dialdehyde prepared from oxidizing a sugar molecule to form ring-opened raffinose, o-raffinose (23). O- raffinose polymerized hemoglobin has good P50 without the need for additional 2,3-DPG analogue. This group is starting their Phase III clinical trial.(Update: Phase III in coronary surgery requiring about 1,000 ml has been completed in Canada and the United Kingdom and awaiting regulatory agencies approval)

    (ii) Intramolecularly crosslinked hemoglobin. The crosslinkers described above can be used for both intermolecular andintramolecular crosslinkage. Studies have been carried out to specifically crosslink hemoglobin molecules intramolecularly(17, 24). A bifunctional agent, 2-Nor-2-formylpyridoxal 5-phosphate which is also a 2,3-DPG analogue can intramolecularly crosslink the 2 beta subunits of the hemoglobin molecules (18). Another 2,3-DPG pocket modifier, bis(3,5-dibromosalicyl) fumarate (DBBF) intramolecularly crosslinks the 2 alpha subunits of the hemoglobin molecule (25). This prevents dimer formation and also improves P50 . Baxter has not continue clinical trial on this intramolecularly crosslinked hemoglobin and is now working on a second generation recombinant hemoglobin. Many other bifunctional 2,3-DPG pocket modifiers are being studied (5-11).

    (iii) Conjugatedhemoglobin is the crosslinking of hemoglobin to polymers (2-4) . The use of soluble polymers resulted in soluble conjugated hemoglobin with good circulation time(28-30). These are now in clinical trial.

    (iv) Recombinant hemoglobin: This is based on genetic engineering of E.coli to result in the prodcution of hemoglobin hemoglobin with good P50 and that retains its tetrameric configuration after infusion. They have successfully prepared a second generation recombinant hemoglobin in which the receptor site for nitric oxide has been blocked. This has resulted in a preparation that does not cause vasoconstriction when infused into experimental animals. (See Lemon's group in Nature Biotechnology, July 1998 issue)

    Circulation time of modified hemoglobin:
    Removal of polyhemoglobin and conjugated hemoglobin after infusion is mainly by the reticuloendothelial system. The half time of polyhemoglobin in the circulation is about 25 to 30 hours. Conjugated hemoglobin stay in the circulation even longer. Intramolecularly crosslinked hemoglobin escapes more rapidly from the circulation and therefore has a shorter circulation time. Survival time in the circulation depends on the dose and the animal species. This time is much shorter than that of red blood cells. However,this is enough for most of the shorter term uses described earlier. For example, all three types of crosslinked hemoglobin are effective in animal studies of hemorrhagic shock and isovolemic exchange transfusions (8-11)


    6. Present status
    Crosslinked hemoglobin is likely to be the first modified hemoglobin ready for routine clinical use. Initial problems which have now been mostly solved were related to potential toxicity and the problems that animal safety studies do not reflect exactly human response. Most of these problems have now been solved by extensive basic studies on hemoglobin (8-11,31-34). In addition, an in-vitro screening test was developed to bridge the gap between animal safety studies and human response (34). This is based on testing the effect of adding 0.1 ml of modified hemoglobin to 0.4 ml of human plasma in a test tube, then analysing C3a to see if there is any complement activation(34). Earlier results of clinical trials have been described (35-38). The most recent clinical trial update is in the next section.

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