Theresa Nester, M.D. and
Marcus Simpson, M.D.
development of a “perfect” blood substitute has been in progress for
many years. Such a product would have advantages over human red cells that
included rapid and widespread availability, fewer requirements with regard
to storage, transport, and compatibility testing, a longer shelf life, and a
more consistent supply. An ideal substitute would be less antigenic than
allogeneic red cells, and would have less risk of disease transmission. Two
main types of blood substitutes are in development, hemoglobin solutions and
perfluorocarbon emulsions. Of the hemoglobin solutions, two products are in
phase III clinical trials, and the companies behind the products predict FDA
approval in the near future.
cell-free hemoglobin has known limitations, such as: an oxygen affinity that
is too high for effective tissue oxygenation; a half-life within the
intravascular space that is too short to be clinically useful; and a
tendency to undergo dissociation into dimers with resultant renal tubular
damage and toxicity. Because of these limitations, hemoglobins used to make
solutions must be modified. A number of modification techniques have been
developed. Hemoglobin can be
cross-linked (a covalent bond between 2 globin chains is made through
chemical modification), and then polymerized using reagents such as
glutaraldehyde. These modifications result in a product that has a higher
P50 than that of normal hemoglobin, and an increase in the plasma half life
of up to 30 hours. The source of the hemoglobin used for the solutions can
be human (outdated donated blood), bovine, or recombinant. The solution is
prepared from highly purified hemoglobin, and taken through processes which
eliminate phospholipids, endotoxins, and viral contaminants.
two products are in advanced clinical trials. Hemolink®
by Hemosol Inc. (Toronto, Ontario (416)-798-0700) is a hemoglobin solution
that contains cross-linked and polymerized human hemoglobin. The
intravascular half-life is 18 to 20 hours. The mode of excretion is not
entirely clear, but a small amount is renal. Phase I clinical trials in
healthy male volunteers showed that the drug is fairly well tolerated, with
abdominal pain of moderate to severe intensity at doses greater than 0.4
mg/kg. This abdominal pain was alleviated with muscle relaxants. A
dose-dependent increase in mean arterial pressure was also seen (1).
According to the company, 8 clinical trials have been completed, including a
pivotal phase III trial in CABG patients in the United Kingdom and Canada. A
phase III clinical trial in CABG patients is currently underway in the
(HBOC-201) by Biopure (Cambridge, Massachusetts (617)-234-6500) is also in
phase III clinical trials. This hemoglobin solution contains cross-linked
and polymerized hemoglobin, however the source of the hemoglobin is bovine.
The intravascular half-life is approximately 24 hours, and the excretion is
non-renal. Administration of the solution to 10 patients with severe anemia
resulted in a 60% survival rate at hematocrits as low as 4.4%. The authors
did emphasize that the product served as a bridge over days, until blood
became available, or the patient’s own red cells were regenerated (2). As
with all hemoglobin solutions, administration of Hemopure®
leads to vasopressor effects that may increase systemic and pulmonary
vascular resistance with resultant decreases in cardiac index. The use of
HBOC-201 in a small study of patients undergoing pre-operative hemodilution
for vascular surgery showed limited efficacy (3). More studies are warranted
to determine whether or not this type of solution can be used in patients
undergoing pre-operative hemodilution for other procedures.
stated above, the main potential adverse effect of these solutions is an
increase in systemic and pulmonary vascular resistance that may lead to a
decrease in cardiac index. Decreases in the cardiac index may impair
optimum oxygen delivery and outweigh the advantage of an oxygen-carrying
solution (3). One of the main mechanisms underlying such vasopressor effects
is cell-free hemoglobin acting as a scavenger of nitric oxide. Animal
studies show that if nitric oxide is placed back into the system, the
vasopressor effects are reversed. In general the patient populations
currently chosen for studies with these solutions are relatively stable, and
may be undergoing high blood-use surgery such as elective AAA repair or
orthopedic surgery. One study examined the utility of these solutions in the
acute resuscitation phase of unstable trauma patients. However the study
design was poor and any role of the solutions in influencing ultimate
patient outcome was unclear (4). Further trials in unstable trauma patients
have not been attempted, thus the benefit or harm of hemoglobin solutions in
these patients stands as an unanswered question.
general, these solutions have been shown to reduce or eliminate the need for
allogeneic blood transfusions in patients undergoing orthopedic surgery,
elective abdominal surgery, and coronary artery bypass graft surgery.
Hemoglobin solutions may also serve as a bridge to transfusion in patients
for whom blood is temporarily difficult to find. They may also serve as a
bridge in the temporary support of a patient who will not accept blood and
who has a reasonable chance of recovering an adequate hemoglobin/ hematocrit
within a few days.
major limitation of hemoglobin solutions is the short intravascular
half-life. A transfused red cell can persist in the circulation for several
weeks in a patient with no active bleeding or hemolysis. A hemoglobin
solution, in comparison, can last several hours and requires frequent
replacement. As these solutions are not yet available, the price compared to
the cost of a unit of blood is unknown.
these solutions have a dark red color, they can hinder the ability of blood
bank staff to obtain an ABO type or antibody screen once the solution has
been infused. It is highly recommended that a patient sample be sent to the
blood bank for type and screen prior to infusion of the hemoglobin solution.
emulsions contain synthetic fluorinated hydrocarbons that are capable of
dissolving oxygen and delivering oxygen to tissues. The transport and release of gases by perfluorocarbons is
based on physical solubility, and the quantity of gas dissolved is linearly
related to its partial pressure. Because the hydrocarbons are immiscible in
water, they require administration as an emulsion. They are chemically
inert, and are not metabolized in vivo. The intravascular half-life depends
on the molecular weight of the compound, but in general is hours to days.
The compounds are eliminated unchanged by the lungs after passing through
the reticuloendothelial system. Ongoing clinical trials show a transient and
dose-dependent flu-like illness, and transient decrease in platelet count as
the main adverse effects. Oxygent®
by Alliance pharmaceutical corporation (San Diego, CA (858)-410-5200) is
currently in phase II clinical trials.
solutions contain modified hemoglobins that have comparable properties to
normal adult hemoglobin. Two solutions containing cross-linked, polymerized
hemoglobin are in phase III clinical trials. The main adverse effects of the
solutions stem from the ability of cell-free hemoglobin to scavenge nitric
oxide. These effects include an increase in vascular resistance with
subsequent decrease in cardiac index. The major limitation of these
solutions, compared to red cells, is their short intravascular half-life.
Because of this limitation, hemoglobin solutions serve mainly as a bridge to
transfusion, rather than as a replacement for blood.
emulsions are inert compounds, capable of dissolving and delivering oxygen
to tissues. Phase II clinical trials are ongoing.
Currently the half-life of these compounds is hours to days, which is
significantly shorter than the lifetime of a transfused red cell.
Carmichael F.J.L. et al. A phase I study of oxidized raffinose
cross-linked human hemoglobin. Crit Care Med 2000; 28: 2283-92.
Jacobs E.E. et al. Use of Hemoglobin Based Oxygen Carrier-201 when
blood is not available or not acceptable. Transfusion 2000; 40: 41S.
Kasper S.M. et al. The effects of increased doses of bovine
hemoglobin on hemodynamics and oxygen transport in patients undergoing
preoperative hemodilution for elective abdominal aortic surgery. Anesth
Analg 1998; 87: 284-91.
Koenigsberg D. et al. The efficacy trial of diaspirin cross-linked
hemoglobin in the treatment of severe traumatic hemorrhagic shock. Acad
Emerg Med 1999; 6: 379-80.
Creteur J. et al. Hemoglobin solutions- not just red blood cell
substitutes. Crit Care Med 2000; 28:3025-34.
Winslow R.M. Diaspirin cross-linked hemoglobin: Was failure predicted
by preclinical testing? Vox Sang 2000; 79: 1-20.
B. et al. Red blood cell substitutes: fluorocarbon emulsions and haemoglobin
solutions. British Medical Bulletin 1999; 55: 277-98.