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Blood On Tap: Part 1: History in the Making

Emergency services around the United States are about to become part of the front lines in the race to bring to market the first blood substitute with oxygen-carrying capabilities. Take a look inside the high-tech world of biopharmaceuticals and the innovative pioneers who are chasing after a scientific holy grail: a synthetic substitute for blood. In the process, they have made and lost fortunes, advanced our understanding of the nature of blood and launched one of the biggest ethical controversies in modern medical history. As phase three clinical trials move to the prehospital arena, biotechnology firms are staking everything on the notion that they're about to change the way we treat trauma patients. They may be right.

Making History (October 2003)

Craig Gravitz, chief paramedic for the Denver Health Paramedic Division, carries a medium-sized ice chest to the front row of the classroom for closer inspection. "We're sorry we couldn't get anything smaller than this," he says, "but it needs several layers of insulation." He cracks the seal on the chest, digs through the layering and holds high a 500cc IV bag marked with a lot number.

Gravitz continues: "This isn't the actual product, but this is exactly how it will be packaged."

"What does the real stuff look like?" asks Will Dunn, a Denver Health paramedic in the fourth row.

With an almost imperceptible grin, Craig says, "It looks like blood."

Scattered around the main auditorium of the Rita Bass Center for Trauma and EMS Education are the paramedics of the Denver Health Paramedic Division. The product in question is Polyheme, an oxygen-carrying blood substitute that promises to replace saline as the fluid of choice in trauma resuscitation. In the coming months, the paramedics of Denver Health will embark on the first prehospital trial of an oxygen-carrying blood substitute in EMS history.

It's no accident that Evanston, IL-based Northfield Laboratories, the creator of Polyheme, chose Denver Health to be one of the first agencies to carry their product into the field. Since the early 1970s, Denver's paramedics have had a reputation for being some of the best trauma paramedics in the world. Their flagship Level I trauma center, The Denver Health Medical Center, has been involved in Polyheme research for close to 10 years.

Polyheme is a front-runner in a field of intravenous solutions that the FDA has classified as "oxygen therapeutics": blood-replacement products with catchy names like Oxygent, Hemopure and Polyheme. These intravenous solutions not only replace blood volume, they mimic the oxygen-carrying capacity of whole blood without the inherent complications that accompany human blood transfusion. The end result is adequate volume replacement while maintaining critical tissue and organ oxygenation.

Controversies in Fluid Resuscitation

Many field providers have sensed that there is something fundamentally flawed in the current practice of high-volume isotonic fluid resuscitation. This isn't a new revelation. The debate over how to best replace lost blood volume in the absence of blood has been waged for years, and many schools of thought have come and gone. The hot topic today is low-volume fluid resuscitation.

Dr. Steven A. Gould, Northfield Laboratories' CEO, explains the two sides of the issue: "The controversy began with some work suggesting that fluid restriction, or delayed resuscitation, was the way to go," he says. "Keep in mind that those studies were done in an urban setting with very short transport times. The other category is vigorous resuscitation. Just give as much as you can give. I think the truth lies somewhere in the middle."

Fluid restriction advocates argue that high volumes of saline increase the blood pressure while negatively affecting clotting ability—a double whammy that works against the body's own defense against traumatic bleeding. Defenders of high-volume resuscitation argue that, while the low-volume resuscitation research is interesting, there aren't enough hard clinical data to change the standard of care and, while far from ideal, saline is the best that we currently have to offer.

Both sides agree that dumping large amounts of saline into a patient until their blood resembles watered-down cherry Kool-Aid is ineffective at best, and a better solution would be a welcome change. Enter the age of oxygen therapeutics.

Blood Simple

In a sample tube, blood seems deceptively basic. When it's spun in a centrifuge, some of blood's true complexities begin to emerge. The blood will divide into three distinct bands. The pale yellow band at the top is plasma, the viscous glue that holds the suspended components of blood together. Plasma carries proteins, electrolytes, lipids and carbohydrates through the vascular system, playing a critical role in regulating pH, osmotic pressures and glucose levels. The thin intermediary layer is a collection of platelets and white cells. These are our clotting factors and immunity, respectively. The thick, dark layer across the bottom is made up of red cells; within each red cell is the chemically complex protein molecule known as hemoglobin.

It is this complex nature of blood that causes scientists to shudder at terms like "artificial blood." We have never come close to synthetically duplicating all of blood's unique properties and functions and most believe we never will. Products like Hemopure, Polyheme and Oxygent earn the title "oxygen therapeutic" because they attempt to duplicate one critical function of blood: the transport of oxygen to the cells and waste gases away from them. At present, the scientific community is divided into four distinct schools of thought regarding where to find a surrogate for hemoglobin's unique abilities.

Expired Human Blood

Large amounts of the nation's blood supply expire before they can be used. These expired lots are purchased from the American Red Cross and other donation centers and harvested for their hemoglobin. One unit of hemoglobin can be produced from every two units of discarded whole blood. Polyheme is an example of an expired human blood product.

Proponents of this technique feel that there will always be a ready supply of unused red blood cells, especially from plasma centers that pay for donations. Some critics are not as confident that dependence on human donors is a good long-term solution.

They point out that the final product lacks 2,3 DPG, a molecule necessary for human blood to off-load oxygen at the cellular level. Some feel the lack of 2,3 DPG in expired human blood products may make the end product less effective.

"This gets into an interesting physiologic discussion on the role of oxyhemoglobin affinity," says Dr. Gould, who is quick to refute the oft-heard claim. "There is no DPG in Polyheme, so we use PLP (pyridoxal phosphate), an organic phosphate that works like DPG. However, DPG has a temporary effect and PLP has a permanent effect, so I think the argument is overstated. Polyheme is very effective at oxygen unloading. Perhaps more so than red cells."

Bovine Hemoglobin

Cattle 18 months old and younger are maintained in controlled environments where everything they are exposed to is rigorously monitored. These cows become the donors of bovine hemoglobin. Hemopure is an example of a harvested bovine hemoglobin product.

Critics are leery about the possibility of disease transmission from donor cows to the final human recipients, but advocates for this technique feel that bovines are a more stable, controlled and reliable source of blood products than humans. As Thomas Moore, president and CEO of Cambridge, MA-based Biopure Corporation, likes to point out, "We know where our cows have been on Saturday night." They also emphasize that these products will not be subject to the demand shortages that our current blood supplies experience.

Another huge selling point for bovine hemoglobin products is their long-term stability at room temperature. Hemopure can be stored for years at room temperature, and has remained chemically unchanged through freezing and boiling tests, a serious advantage for future prehospital and military users.

Recombinant Hemoglobin

A genetically modified version of the hemoglobin molecule is inserted into common bacteria, such as E-coli. The bacteria are then fermented to produce large quantities of the new hemoglobin, and the final product is purified to leave behind only the hemoglobin molecules. While the process sounds a little like science fiction, it is used routinely in the production of recombinant insulin.

The only recombinant product to pass into phase two research was Optro, produced by the Somatogen Corporation out of Boulder, CO. When Baxter Healthcare Corporation acquired Somatogen, production of Optro was halted in favor of other technologies. No other large firms are exploring recombinant techniques at this time.

Perfluorocarbon Emulsions

Most everyone has seen pictures or video clips of mice swimming around in "liquid oxygen." The liquid is an oxygen-saturated perfluorocarbon (PFC) solution. PFC molecules are 1/100 the size of a red blood cell and can saturate 50 times more oxygen than hemoglobin. Oxygent is an example of a perfluorocarbon solution.

While the numbers make PFCs a tantalizing prospect, critics point out that PFCs don't mix well with blood and need to be mixed with oils or lipids to remain stable in the intravascular environment. Patients are also required to breathe 100% oxygen to maintain the effectiveness of the solution, creating another host of problems. Most researchers remain skeptical about PFC's practical applications in the trauma setting.

Better Than Blood?

Biochemists and researchers may be shy about using terms like "artificial blood," but they have no qualms about suggesting that these products may, in many ways, be better than blood. The clinicians who transfuse whole blood products are quick to remind us that allogeneic whole blood is not a volume replacement panacea.

Receiving six or more units of whole blood in the first 12 hours post-injury is an independent risk factor for multiple organ failure. Add to that the increases in nosocomial infection rates, the potential for viral transmission and the king of whole blood product errors, incorrect blood typing, and blood's limitations become clear. Oxygen therapeutics boast several characteristics that make them not only safer and more convenient for in-hospital use, but possible to carry into the prehospital setting.

Jeff Long, RRT, a critical care respiratory therapist at Denver Health Medical Center, has been involved in oxygen therapeutics research for several years. While he often speaks in the controlled and understated language of medical research, his excitement regarding the future potential of oxygen therapeutics occasionally breaks through. When I pressed him for details on what makes oxygen therapeutics like Polyheme superior to whole blood products, he says, "First, I would certainly say that it is superior to blood in its ease of administration. That's a strong statement, but because it is universally compatible, this product does not need to be typed and cross-matched, and that is probably its greatest advantage. There is no preparation. You walk over to where it is stored, walk it to the patient and put it through an IV. There is no risk of cross-reaction, as there is if someone gets the wrong blood type. There is no special equipment needed, no filters—it is really very simple to use."

I asked if the risk of viral transmission is still a concern.

"Any product that uses blood as its primary raw material carries at least a theoretical risk of viral transmission," he concedes. "We believe that the manufacturing and filtration process, coupled with the polymerization process, essentially sterilizes the product. It cannot be said that there is no risk of viral transmission, but the risk is greatly reduced. I personally believe the risk to be zero."

Pressing further, I asked the question that had been weighing on my mind. Is this stuff more effective than blood? Could it replace blood altogether?

Long is quick to answer. "These types of products are not going to ever take the place of blood. The half-life of these products is 24 hours. In 48-72 hours, they are out of the system. For that reason alone, they will never replace blood products. They serve as a bridge between the time a patient is first contacted to the time when whole blood is available. That is the key to this study. Polyheme will be given to patients where blood is not available. Ultimately, that is where it will have the most benefit. Whether it is in rural areas or long transport times, anywhere blood is not available and someone is bleeding to death, that is where this product will be most beneficial."

The Challenge Ahead

To hear biopharmaceutical companies tell it, the future acceptance of synthetic blood products is a done deal. Ask the CEOs of companies like Biopure and Northfield Laboratories what challenges lie ahead, and their answers exude the cool confidence of seasoned athletes. From the people in charge of publicly traded companies, a little bravado is forgivable. In a world where investment dollars are crucial and one bad piece of publicity can send a corporation's stock value and investor confidence plummeting, talking about speed bumps in the road to success can be uncomfortable.

At Biopure's headquarters in Massachusetts, CEO Thomas Moore and Dr. Douglas Hansell, vice-president of Medical Affairs, gather around a conference phone and pick through the delicate question. As the makers of Hemopure, an oxygen therapeutic approved for general use in South Africa, they are well-versed in the challenges of bringing a new product to market.

"The greatest challenge will always be to honor the regulatory process, through which you demonstrate the efficacy of the product by whatever standard the FDA chooses to hold up," says Moore. "In the prehospital setting, in trauma, that expectation is an advantage in mortality compared to the use of saline.

"Conducting a trial in the prehospital environment is much more chaotic and stressful than in prescheduled surgery," he adds. "Emergency personnel will do whatever it takes in the best interest of the patient. That makes the structure of a clinical trial very demanding when you are on the run and doing what you can for the patient's survival."

"Another challenge," adds Dr. Hansell, "is in changing the way clinicians think. This is a drug that carries oxygen. This is not a replacement for blood; this is a drug that replaces the function of red cells. Learning to use that correctly will be a shift for clinicians—but a very exciting one."

The Dawn of New Blood

Throughout history, blood has been viewed as the carrier of our vital human spirit, as well as the carrier of our most deadly diseases. The story of blood is one of change and advancement. We have learned how to remove it, separate it, replace it, store it, send it around the globe and safely transfuse it into another human being. We now stand on the threshold of a new breakthrough that is bound to be one of the top 10 scientific advances of the 21st century: replicating the properties and functions of blood.

As with any new advancement, the element that most ignites the imagination about oxygen therapeutics is their potential. When we look at oxygen therapeutics in the current context of volume replacement with oxygen-carrying capacity, the future of trauma care becomes an exciting prospect. When we see oxygen therapeutics as drugs that can carry oxygen beyond the limitations of the red blood cell, the horizon explodes with possibilities.

The pioneers of oxygen therapeutic research today see its vast potential to save the lives of trauma victims. The pioneers of oxygen therapeutics' future see their potential to treat a vast array of ischemic conditions. They talk about hemoglobin molecules passing through vascular blockages where red cells can't go to oxygenate starving tissue. If they're right, these products could be the ultimate first-line medication for a long list of ischemic conditions, from shock states to myocardial infarction to stroke. While it is difficult to say how long it will take before oxygen therapeutics become a standard of care, we can say with confidence that they are here to stay, and their long-term influence on medicine will be monumental.

Bibliography

  • Artificial Cells and Organs Research Center, McGill University, Quebec, Canada. www.artcell.mcgill.ca.
  • Biopure Corporation, Cambridge, MA. www.biopure.com.
  • Cohn SM. Hemoglobin-based red cell substitutes. In: Topic Review of the Month. Ryder Trauma Center, Online education page, 2001.
  • Daily J. Dailey's Notes on Blood. Arlington, VA: Medical Consulting Group, 1996.
  • Denver Health Paramedics to Participate in Clinical Trial of Oxygen-Carrying Blood Substitute. In: EMSNetwork News, www.emsnetwork.org.
  • Gould S, Moore E. The life-sustaining capacity of human polymerized hemoglobin when red cells might be unavailable. J Am Coll Surg 195:(4):445-451, 2002.
  • Gould S. J Am Coll Surg 195:(4):453-455, 2002.
  • Gould S, Moss G. Clinical development of polymerized hemoglobin as a blood substitute. World J Surg 20:1200-1207, 1996.
  • Manning JE. Bovine hemoglobin-based oxygen carrier (HBOC-201) for resuscitation of uncontrolled, exsanguinating liver injury in swine. Shock 13:(2):pp 152-159, 2000.
  • McNiel JD. Hypotensive resuscitation using a polymerized bovine hemoglobin-based oxygen carrying solution (HBOC-201) leads to reversal of anaerobic metabolism. J Trauma 50:1063-1075, 2001.
  • Moore E. Blood substitutes: The future is now. J Am Coll Surg 196(1):1-3, 2003.
  • Northfield Laboratories Inc., Evanston IL. www.northfieldlabs.com.
  • Owens TM. Limiting initial resuscitation of uncontrolled hemorrhage reduces internal bleeding and subsequent volume requirements. J Trauma 39: 200-209, 1995.
  • Rabinovici R. The status of hemoglobin-based red cell substitutes. IMAJ Vol. 3, Sept 2001.
  • Stern SA. Effect of blood pressure on hemorrhage volume and survival in near fatal hemorrhage model incorporating a vascular injury. Ann Emerg Med 22:155-163, 1993.
  • Starr D. Blood: An Epic History of Medicine and Commerce, New York, NY: HarperCollins Publishers Inc, 1998.
  • Winslow RM. Hemoglobin-Based Red Cell Substitutes. Baltimore, MA: The Johns Hopkins University Press, 1992.

Next Month: Blood On Tap
Part Two: An Ethical Dilemma in Emergency Research
When Denver Health paramedics bring oxygen therapeutic research into the prehospital arena, they will be enrolling patients as study participants using a new FDA regulation (21 CFR 50.24) that allows for medical research to be conducted without prior patient consent. Touted by clinicians as a long-awaited necessity in emergency research, vilified by the media as a breach of medical ethics, how important is 50.24 to the future of emergency care, and would the Polyheme trial be possible without it?

Players in the Blood Game

A who's who list of the most well-known oxygen therapeutics in the past decade and their current status.

Polyheme/Northfield Laboratories
Content: Crosslinked glutaraldehyde—polymerized human hemoglobin.
Current status: Phase III clinical trials in prehospital
trauma applications.
Positives: Universal compatibility. Strong early clinical data in traumatic etiologies. High level of purity. Prolonged shelf life.
Negatives: Blood typing post-administration difficult. Dependent on donor blood supply. Possible disease transmission.* Possible immune reaction.**
Interesting fact: Physicians have replaced up to 200% of a patient's total blood volume with Polyheme without complication.

Hemopure/Biopure Corporation
Content: Crosslinked glutaraldehyde—polymerized bovine hemoglobin.
Current status: Approved for use in South Africa. Phase III clinical trials in orthopedic surgery. Pre-clinical for trauma applications.
Positives: Universal compatibility. No refrigeration required. Abundant source material. High level of purity. Prolonged shelf life.
Negatives: Blood typing post-administration difficult. Possible disease transmission.* Possible immune reaction.**
Interesting fact: The military is paying close attention to Hemopure's development due to its ability to remain stable for years at extremes of heat and cold. An advantage for battlefield medicine.

Oxygent/Alliant Pharmaceuticals & Baxter Healthcare Corp.
Content: Second generation perfluorocarbon emulsion.
Current status: One phase III surgical trial underway in Europe. Multiple other surgical trials in phase II in the U.S. and Europe.
Positives: Universal compatibility. Pharmaceutical-grade purity. No need to harvest source materials. Prolonged shelf life. No refrigeration required.
Negatives: While shown to reduce the need for additional blood products in surgical settings, perfluorocarbons have never been tested on traumatic hypovolemia patients.
Interesting fact: PFCs are biologically inert and not broken down in the body. They are exhaled within 48 hours of administration.

Hemolink/Hemosol Inc.
Content: Crosslinked O-Raffinose—polymerized human hemoglobin.
Current status: Phase III clinical trials halted in June 2003 due to increased myocardial infarction rates among Hemolink recipients. Clinical trials on hold.
Positive: Universal compatibility. High level of purity. Prolonged shelf life.
Negatives: Blood typing post-administration difficult. Dependent on donor blood supply. Possible disease transmission.* Possible immune reaction.**
Interesting fact: Before being pulled from the market, Hemolink had been administered to over 500 patients in eight different phase III surgical trials. No date has been set for continuation of Hemolink trials.

Optro/Baxter Healthcare Corporation (originally Somatogen Inc.)
Content: Escherichia-Coli recombinant hemoglobin.
Current status: After Baxter acquired Somatogen in 1998, research was discontinued in favor of other technologies. Positives: Universal compatibility. High level of purity. Prolonged shelf life.
Negatives: Unknown. Product never reached a large cross-section of recipients.
Interesting fact: Optro is the only major oxygen therapeutic discontinued for marketing and strategic issues, not performance-based issues.

Fluosol-DA/Green Cross Corporation First Generation Content: Perfluorocarbon emulsion.
Current status: FDA-approved for use in angioplasty. Green Cross terminated production in 1994 due to excessive and uncontrolled side effects.
Positives: Universal compatibility. Pharmaceutical-grade purity. No need to harvest source materials.
Negatives: Ineffective at increasing oxygen delivery. Multiple side effects including disruption of normal pulmonary surfactant. Poor shelf life.
Interesting fact: The first oxygen therapeutic to gain an FDA approval. Fluosol paved the way for the next generation of perfluorocarbon research.

Hemassist/Baxter Healthcare Corporation
Content: Crosslinked human hemoglobin.
Current status: Phase III clinical trials halted in 1996 when a significantly larger number of deaths occurred in the Hemassist recipient group than the control group. Production stopped.
Positives: Universal compatibility. High level of purity. Prolonged shelf life.
Negatives: Unexplained side effects including mild hypertension. Dependent on human donor supply. Possible disease transmission.* Possible immune reaction.** Blood typing post-administration difficult.
Interesting fact: The first medical product tested under the 1996 FDA ruling (21 CFR 50.24) allowing some patients to participate in medical research without their prior informed consent.

* No patients receiving this product have ever demonstrated any disease transmission.
** No patients receiving this product have ever demonstrated any immune reaction.

Terminology Of Oxygen Therapeutics

Hemoglobin-Based Oxygen Carriers or HBOCs: A catch-all term for any oxygen therapeutic that utilizes the hemoglobin molecule as its primary oxygen-carrying unit.

Stroma-Free Hemoglobin: As part of the production process for HBOCs, hemoglobin is separated from the red blood cell in a saline solution. The leftover cellular debris of the red blood cell (stroma) is filtered away, leaving the hemoglobin molecule behind. Free hemoglobin that has been separated from red blood cell stroma is referred to as stroma-free hemoglobin.

Cross-linked: Stroma-free hemoglobin, if left to its own devices, rapidly breaks down into dimers and monomers. These very small molecules cause all sorts of problems, including severe kidney dysfunction. Native hemoglobin dimers and monomers can be genetically linked into tetramers. The larger tetramer retains its function without the associated problems and is considered “cross-linked.”

Polymerized: Simple cross-linked hemoglobin tetramers still tend to cause significant vasoconstriction. The underlying cause of this vasoactivity is a matter of debate. To further stabilize stroma-free hemoglobin, surface amino acid groups are linked by reagents, such as glutaraldehyde, causing multiple tetramers to bind together. The final product is considered polymerized.

Recombinant: The gene for human hemoglobin is inserted into bacteria, such as E-coli, and cultured. The human hemoglobin is then isolated from the culture. Molecules such as hemoglobin are called recombinant when artificially created by this process. This process also allows for manipulation of the gene itself to create variant forms of hemoglobin and other molecules.

Perfluorochemicals (PFCs): Synthetically modified hydrocarbons, PFCs are inert chemicals that are 1/100th the size of a red blood cell. These solutions have the capacity to dissolve up to 50 times more oxygen than plasma.

Emulsion: PFCs in their most basic form do not mix well with blood. To overcome this, PFCs are suspended (emulsified) in lipids or oils. The suspension is referred to as a perfluorocarbon emulsion.

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