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14 Blood Conservation Strategies andBloodless Medicine
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133
transport properties of LtEc were believed to be unaffected
by storage at high temperatures or oxidation [36]. The stability of Lumbricus terrestris erythrocruorin can also be
increased via poly(acrylic acid) conjugation [37]. The
development of red blood cells from stem cells is currently
also underway. The use of pluripotent stem cells could allow
for the mass production of red blood cells in the future. High
production cost is the strongest limiting factor, and this
could diminish over time [38].
Summary
Blood transfusions, while potentially life-saving, are fraught
with risks and refusal by patients and sometimes unavailable.
Blood transfusions can cause signicant morbidity and mortality. Bloodless medicine involves preoperative assessment
of anemia and minimization of iatrogenic/surgical blood
loss. Strategies are readily employed in a variety of patients
including the Jehovah’s witness, the orthopedic patient, and
the cardiac patient. Many blood substitutes are being developed to provide red blood cells’ oxygen-carrying capability.
As bloodless medicine continues to advance, the need for
blood transfusions will decrease.
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When Blood Is Not anOption: Care
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oftheJehovah’s Witness Patient
JustinB.Feit andSethPerelman
15
Clinical Case Description
A fty eight-year-old female Jehovah’s Witness with medical history signicant for ESRD not yet on dialysis, COPD,
presenting with worsening shortness of breath, found to have
severe mitral regurgitation and severe tricuspid regurgitation.
After consultation with surgeons, decision was made to proceed with an open mitral valve and tricuspid valve replacements. She is referred to presurgical testing for medical and
surgical optimization prior to surgery.
Introduction
Perioperative blood management is a crucial aspect of the
anesthesiologist’s clinical duties. While it is important to
avoid/prevent perioperative anemia due to its morbidity and
mortality [1], blood product administration has its own consequences [2], including transfusion reactions [3], pathogen
transmission [4], immunomodulation [5], transfusion-related
acute lung injury (TRALI) [6], and transfusion-associated
circulatory overload (TACO) [7]. There are indications for
specic blood product transfusions, including need for
increased oxygen-carrying capacity and tissue oxygenation
and treatment of coagulopathy secondary to factor deciencies or platelet dysfunction, for example [8, 9].
Despite situations in which blood product transfusion is
indicated (and withholding of these products can be fatal),
there are certain patients that will refuse blood product trans-
J. B. Feit
NYU Langone Health, NYU School of Medicine, Department of
Anesthesiology, Perioperative Care, and Pain Medicine,
New York, NY, USA
e-mail: Justin.Feit@nyulangone.org
S. Perelman (
NYU Grossman School of Medicine, Department of
Anesthesiology, Perioperative Care and Pain Medicine,
New York, NY, USA
e-mail: Seth.perelman@nyulangone.org
*)
fusion based on religious beliefs; among these patients, the
most notable population includes patients of the Jehovah’s
Witness faith. These patients pose a particular challenge
among anesthesiologists with respect to perioperative blood
management due to their refusal of certain blood products
and limited intraoperative treatment options.
Blood Transfusions
The modern history of blood transfusions began in the mid1660s when English physician Richard Lower experimented
with transfusing blood between dogs shortly before physician
Jean Denis experimented with transfusing humans using blood
taken from dogs [10]. In the late eighteenth century, Joseph
Priestley described red blood cells as capable of carrying oxygen [11], shortly before French chemist Antoine Lavoisier
described the importance of oxygen in respiration [12]. Further
advances in blood transfusion occurred in the early nineteenth
century with English obstetrician James Blundell, the “Father
of Autotransfusion”; it was discovered that giving back blood
lost during surgery was not only safer than transfusing animal
blood to humans, but also that autotransfusion improved mortality in massive surgical hemorrhages [13].
Despite improved outcomes demonstrated by Blundell
with human transfusion in the nineteenth century, there were
many issues that needed additional research including transfusion reactions and blood product storage. In the early
twentieth century, Karl Landsteiner, a German physician,
began elucidating the ABO red blood cell antigen system
which helped decrease the amount of deadly transfusion
reactions signicantly [14]. Storage of blood products was
increased to almost 3weeks through the discovery of adding
citrate (by Richard Weil) [15] and dextrose (by Peyton Rous
and JR Turner) [16]. Blood transfusions became more practical for humans after World War II with the creation of the
modern blood bank by Drs. Bernard Fantus and Lindon Seed
out of Chicago, IL [17].
© Springer Nature Switzerland AG 2021
C. S. Scher et al. (eds.), Essentials of Blood Product Management in Anesthesia Practice,
https://doi.org/10.1007/978-3-030-59295-0_15
135
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J. B. Feit and S. Perelman
Over the 300years since Dr. Lower began his experimentation, there have been numerous further advances in transfusion medicine with respect to efcacy and safety. To this day,
blood transfusions are the most common invasive procedure
performed in the United States across all of medicine [18].
Blood transfusions can be lifesaving in many surgical environments, especially with increased morbidity and mortality
associated with anemia, coagulopathy, and catastrophic surgical bleeding. However, despite well-recognized indications for blood transfusion, patients who receive a blood
transfusion during their hospital stay for whatever reason are
also more likely to have increased length of stays and mortality within 28days [19], and the efcacy of allogeneic transfusion has come into question.
It is important for anesthesiologists to know what types of
products are available to administer and their specic indications. The four most common blood products given in the
perioperative period are red blood cells, platelets, fresh frozen plasma, and cryoprecipitate [20]. Red blood cells are
used to increase the oxygen-carrying capacity in patients
with anemia or with signicant blood loss that impacts tissue
oxygenation [21]. Platelets are commonly administered to
treat or prevent bleeding in patients with low platelet counts
or with platelet dysfunction [22]. Fresh frozen plasma (FFP)
is the frozen version of the uid portion of whole blood; FFP
includes all of the coagulation factors with the exception of
platelets [23]. FFP administration is commonly indicated in
the setting of coagulation factor deciency in the presence of
active bleeding [24]; other situations include planned surgery in the setting of abnormal coagulation and thrombotic
thrombocytopenic purpura. If FFP is thawed at 4 °C as
opposed to its normal 37°C, cryoprecipitate is created [25].
While FFP contains all coagulation factors, cryoprecipitate
is made up of brinogen, factor VIII, factor XIII, and Von
Willebrand’s factor [25]. Cryoprecipitate is commonly
administered in the setting of massive hemorrhages associated with hypobrinogenemia, most commonly seen in cardiac surgery, obstetrics, and liver transplantation [25].
There are other blood product derivatives that are also
used in the perioperative period including albumin, individual clotting factors, prothrombin complex concentrate
(PCC), and immunoglobulins.
Jehovah’s Witnesses
The Jehovah’s Witness faith was founded in 1881 by Charles
Taze Russell, a Pittsburgh-based Christian minister [26].
Russell began disseminating his beliefs in Zion’s Watch
Tower and Herald of Christ’s Presence, a monthly religious
magazine publication that was used to spread the teachings
that would eventually become the main principles of the
Jehovah’s Witness faith [26]. With respect to their beliefs
regarding blood management, their teachings are based on
specic passages in the bible, namely, Genesis 9:4, which
states, “Only, you shall not eat esh with its life, that is, its
blood” [27], and Leviticus 17:10, saying, “If anyone of the
house of Israel or of the aliens who reside among them eats
any blood, I will set my face against that person who eats
blood, and will cut that person off from the people” [27].
These passages are interpreted to form one of the main tenets
of the JW religion: their refusal of numerous types of blood
products. As a result, these beliefs have led to multiple challenges in the medical and surgical care of Jehovah’s
Witnesses.
The JW religion includes 2,000,000 followers in the
United States and over 8,000,000 worldwide [18]; it is
likely that an anesthesiologist will encounter a Jehovah’s
Witness as a patient and possibly in a clinical situation
where blood transfusion may be clinically indicated, but
patient beliefs may make this scenario medically and
legally challenging.
Legality
With respect to any patient population, it is important to
understand each specic patient’s requests/beliefs with
regards to their medical care. Regarding blood management
and Jehovah’s Witness patients, their refusal/acceptance of
various blood products is deeply rooted in ancient Biblical
scriptures and subsequently passed down from generation to
generation [26]. With these reasons for refusing certain
blood products even in life-threatening situations, it is imperative as anesthesiologists that we understand and respect the
wishes of this patient population. Even with the widely
believed notion that Jehovah’s Witnesses refuse all types of
blood products, it is important to have an individualized conversation with each patient and clearly delineate which products are acceptable and which products are not acceptable as
they may differ from patient to patient. Generally speaking,
most JW patients will refuse “major blood fractions,” namely,
red blood cells, white blood cells, plasma, and platelets,
while some will accept “minor blood fractions,” including
hemoglobin- based oxygen carriers, interferons, albumin,
cryoprecipitate, and specic clotting factors [28]. Most JW
patients will accept uids (crystalloids/colloids), synthetic
stimulating agents (erythropoietin, thrombopoietin), recombinant factor VIIa, and articial blood substitutes [28].
The reason why certain patients within this population
may accept or refuse certain blood products differs from
patient to patient based on their interpretation of the scriptures, and it is important to document their specic wishes
in order to come up with an acceptable plan for both the
provider and patient before undergoing surgery.
Documenting these wishes in the medical record is of tanta-
15 When Blood Is Not anOption: Care oftheJehovah’s Witness Patient
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mount importance before taking care of this patient population. Consulting your institution’s risk management or the
JW HLS (Hospital Liaison Services) may also be of assistance prior to planned surgical interventions. Not only institutions have legal/risk management services available for
the perioperative period, but also there are specic blood
consent forms that include each type of blood product/substitute and allow the patient to delineate which products are
acceptable or objectionable.
During most patient encounters, there is enough time to
have this discussion with the patient, and it is clear what
products the patient will and will not accept; what about
when there is an emergency or if the patient does not have
capacity to have this conversation? Many Jehovah’s
Witnesses carry a Durable Power of Attorney (DPA) card
that may delineate which products are and are not acceptable in the event of an emergency, but also may designate a
person who will be able to make clear their wishes in the
event that they cannot make their wishes known at that specic time [29]. In the event of a DPA card and health-care
proxy with conicting opinions on treatment options, the
DPA card will ultimately override the health-care proxy. If
no card or health-care proxy is immediately available in an
emergency life-threatening situation, a medical provider
should treat as according to the standard of care, including
transfusion of any clinically indicated blood products or
derivatives [29].
Acceptable andUnacceptable Treatments
As previously mentioned, there are “major blood fractions”
that are generally not accepted by JW patients, and there are
“minor blood fractions” that may be accepted by most JW
patients. There are also products that are often accepted by
most Jehovah’s Witness patients which include uids (crystalloids and colloids), synthetic stimulating agents (erythropoietin and thrombopoietin), recombinant factor VII, and
articial blood substitutes [28]. All of these agents refer to
intravenous “blood substitutes” that are part of overall blood.
Topical hemostatic agents (Avitene™, Tisseel™, etc.) are
generally accepted and may be used as part of surgical hemostasis; these agents typically work by directly activating
platelets and promoting thrombin formation, thus stabilizing
blood clot formation during surgical bleeding. As with other
products, these topical agents should be part of the blood
refusal consent process as some JW may refuse thrombincontaining products.
Additional available treatments for JW patients include
extracorporeal closed loop techniques—acute normovolemic
hemodilution (ANH), cardiopulmonary bypass (CPB), and
dialysis [28]; many of these procedures are acceptable, given
that the circuit is maintained in a closed loop conguration.
ANH involves preemptive removal of blood from a patient
followed by replacement with acellular uid, typically crystalloid or colloid [30]; this process leads to decreased red
blood cell loss during surgery. At the end of surgery, the
removed blood is then transfused back to the patient [31].
Preoperative Assessment
Perioperative assessment is crucial in optimizing this specic patient population. Traditionally, anesthesiologist’s
roles with respect to patient blood management exclusively
occurred in the operating room setting, but it has become
more prevalent over the last 15–20years for the anesthesiologist to be involved in the patient’s optimization in the presurgical period as part of a multidisciplinary team including
surgeons, internists, and hematologists [32].
Part of the preoperative assessment requires an open
conversation regarding what specic products and procedures will be acceptable and which would be objectionable. This discussion is critical in planning for the
perioperative management of the JW especially in situations where blood products may be administered based on
clinical indications. Ideally, this respectful discussion
should happen early in the care of the patient, without the
need to repeat it with each health-care provider encounter,
which could be viewed as disrespectful or at worst
coercion.
While there are indications for preoperative transfusion
for all types of major blood products, red blood cell transfusion is the most common product transfused preoperatively
[18]. Perioperative anemia is not only a risk factor for
increased morbidity/mortality in the perioperative period
[33] but also a predictor of intraoperative and postoperative
red blood cell transfusions[1]; this makes correction of anemia in the Jehovah’s Witness population particularly crucial
to improving their postoperative outcomes. However, there
are opportunities to optimize their hemoglobin levels without using blood products [34]. There are numerous etiologies
of anemia that should be identied and treated, such as irondeciency anemia (iron), megaloblastic anemia (Vitamin
B12, folate), or inadequate erythropoietin synthesis (erythropoietin-stimulating agents) [35]. There are various formulations for these acceptable alternatives, including oral,
intravenous, intramuscular, and subcutaneous, that give this
population options to allow for preoperative optimization
without the need for allogeneic transfusion. The importance
of the early evaluation and treatment of preoperative anemia
should not be limited to the JW population and should be
part of the preoperative evaluation of all patients, but in the
JW patient, it is critical.
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J. B. Feit and S. Perelman
Perioperative Blood Management Strategies
There are many opportunities in the perioperative period to
provide optimal medical/surgical care for these patients
while simultaneously respecting their specic beliefs. Our
obligation as physicians is not limited to a patient’s physical
ailments but also extends to respecting their spiritual beliefs.
In collaboration with the surgeons, it is important to minimize blood loss when possible. For example, use of minimally invasive procedures, intraoperative cell salvage,
arterial tourniquets, acute normovolemic hemodilution, and
permissive hypotension are all strategies that can be
employed in collaboration with our surgical colleagues to
minimize blood loss intraoperatively [1]. Use of interventional radiology when applicable, compared to open techniques, can also minimize blood loss [1].
Maintaining euvolemia is crucial to allow the physiological response to anemia tolerance which includes increased
tissue oxygen extraction, increased cardiac output, and
increased sympathetic response to maintain oxygen delivery
[36]. Supplemental oxygen, along with aggressively optimizing preoperative lung function can help maximize oxygen delivery, especially in low hemoglobin states [28].
Aggressively treating high metabolic demand states both
intraoperatively and postoperatively (i.e., antibiotics for septic shock, mechanical support for cardiogenic shock, uids/
vasopressors for hypovolemic shock, paralysis) minimizes
oxygen demand and thus compensates for potentially lower
oxygen-carrying capacities [28].
Coagulation defects are often easily treated with plasma
and/or platelets, but those products are usually restricted in
the Jehovah’s Witness population. One of the least invasive,
yet most important opportunities to minimize coagulopathies
as anesthesiologists is by maintaining normothermia—hypothermia impairs thrombin generation as part of coagulation
initiation and thus by maintaining normothermia, or more
importantly avoiding hypothermia, can avoid unnecessary
coagulopathies [37]. There are also many pharmacologic
treatments of coagulopathy that can potentially obviate the
need for plasma/platelets; these treatments include prothrombin complex concentrate (PCC), calcium, vitamin K,
tranexamic acid (TXA)/aminocaproic acid, desmopressin,
and recombinant factors among others [36]. Perioperative
consultation with a hematologist can provide further guidance on how to use these treatments should certain reversible
coagulopathies arise intra- or postoperatively.
Minimizing phlebotomy perioperatively minimizes HAA
(hospital acquired anemia), which although may seem inconsequential compared to possibly large intraoperative blood
losses has been shown to lead to worse outcomes compared
with patients with less iatrogenic blood loss [38]. While it is
important to assess a patient’s overall clinical status using
laboratory tests, similar information can be acquired using
more efcient techniques. POC (point-of-care) tests and the
availability of pediatric test tubes can also limit hospital
acquired anemia. Additionally, routine arterial blood gases
for ventilated patients can be replaced by using continuous
end-tidal carbon dioxide monitoring and noninvasive oximetry to assess respiratory status, thus potentially limiting the
need for frequent blood draws [39].
Anemia Tolerance andPatient Outcomes
While it is important to understand how anesthesiologists
can use alternate therapies rather than using “major blood
products,” it is also imperative to understand transfusion
thresholds and how that corresponds to patient outcomes,
especially in the JW population. There are situations during
major hemorrhage and coagulopathy when most providers
will empirically give blood products before getting any lab
tests, as per widely accepted standards of care. However,
there are other instances when time allows for goal-directed
therapy based on POC testing, and it is up to the anesthesiologist to decide how to proceed with this information and
whether a transfusion is indicated. With well-documented
side effects, potential complications, and questionable efcacy of blood transfusions [40], transfusions should not be
threshold based but should be based on clinical symptoms of
anemia or coagulopathy.
What do we tell our patient when she comes to pre- surgical
testing and asks how her religious beliefs will affect her overall outcome? Compared to patients without personal transfusion restrictions, Jehovah’s Witness patients undergoing
cardiac surgery who refuse all major blood products have
similar short-term and long-term mortality [41]. Similarly, for
Jehovah’s Witness patients undergoing cardiac surgery who
refuse blood transfusions, there has been a lower incidence of
postoperative myocardial infarction, shorter time to extubation, shorter length of stay, and reduced costs in both the intensive care unit and the hospital [42]. With careful attention paid
to these patients from the moment they are scheduled for surgery to when they leave the hospital, it is possible to have outcomes similar to those patients who are less restricted in their
blood product acceptance. While these studies may indicate
similar/better outcomes for JW patients compared to the general population, it is important to recognize their limitations,
namely, that most of these studies are observational and that
there are no randomized- control trials that have looked at similar information. Additionally, it is possible and that these JW
patients were not randomized that there were both conscious
and subconscious modications of surgical technique knowing that there are limitations for blood transfusion in the event
of uncontrolled surgical bleeding.
15 When Blood Is Not anOption: Care oftheJehovah’s Witness Patient
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Summary
With respect to our patient scheduled for cardiac surgery,
there are many options for optimization despite the possibility of a high blood-loss surgery. While the surgery is not
elective, it is also not emergent such that there is adequate
time for optimization. Presurgical consultation with an
anesthesiologist is imperative and crucial for minimizing
perioperative morbidity. Patients who are dialysis-dependent are often chronically anemic due to impaired erythropoietin production in interstitial cells found in the renal
cortex. Other etiologies of anemia in patients with endstage renal disease include uremic-induced inhibitors of red
blood cell production and nutritional deciencies (iron,
folate, vitamin B12). Improvement in anemia for this
patient can be accomplished by targeting each of the previously mentioned causes of anemia—use of erythropoiesisstimulating agents (ESA- examples including Aranesp™,
Epogen™), strict dialysis and use of desmopressin to
address uremic platelet dysfunction, and importantly intravenous iron, folate, and vitamin B12 to address possible
nutritional deciencies. Intraoperatively, strategies to minimize blood loss include ANH, cell saver, and the use of
permissible “minor blood products,” if indicated.
Postoperative strategies involve minimization of blood
draws, use of vasopressors if indicated, and continued treatment of postoperative anemia.
Blood management in the Jehovah’s Witness patient
poses particular challenges for the anesthesiologist most
notably their refusal of certain blood products due to religious beliefs. Patients having surgeries in which there is a
high likelihood of moderate blood loss should be evaluated
as soon as possible to assess for the presence and treatment
of preoperative anemia but also to set out expectations for
both the patient and the physician. There are many tools in
our arsenal to deal with this challenging clinical scenario
in high-risk, high blood-loss surgeries within the connes
of honoring a patient’s religious beliefs; with the knowledge of available institutional resources along with a clear
understanding of the patient’s specic wishes, it is possible to have good surgical outcomes while avoiding
transfusions.
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Blood Substitutes andArtificial Oxygen
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Carriers
JacobTiegs
16
History
Experiments using substances to deliver oxygen to tissues
have been conducted since the seventeenth century [1].
Initially, hemoglobin solutions were injected into humans
with very poor results. Morbidity likely arose from free
hemoglobin particles and their negative effects on the GU
system and kidneys in particular. A number of factors contributed to a rebirth in interest for articial oxygen carriers
including increased warfare during the twentieth century and
the identication of blood-born infectious diseases. As blood
transfusion became safer and methods for decreasing the risk
of transfusion-related infections developed, the impetus for
breakthroughs in blood substitutes may have waned.
However, soon a number of companies had promising products that were in the later phases of clinical trials.
Unfortunately, these trials soon ended due to concerns over
ability to get regulatory approval while funding became
scarce [2]. Despite this, the need for blood substitutes and
articial oxygen carriers still exists, and some products continue to be in development.
Ideal Characteristics ofOxygen Carriers
There are a number of characteristics that would be part of an
ideal articial oxygen carrier. First, it would be readily available and able to be mass produced. It would also need to be
safe. This would mean minimal side effects, ability to interact in a non-detrimental way with nitric oxide, and it would
be sterile. The substance would ideally be portable and easily
stored while having a long or manageable shelf life. The
J. Tiegs (*)
NYU Langone Medical Center, Department of Anesthesiology,
New York, NY, USA
e-mail: Jacob.tiegs@nyulangone.org
compound would be able to be given universally to all
patients and be cost effective. This list may seem unattainable and lengthy; however, there are at least two compounds
currently that satisfy most of these requirements.
Current Types ofOxygen Carriers
To date, there are two main categories of oxygen carriers.
Hemoglobin-based oxygen carriers, or HBOCs, are derived
from bovine or human blood. First, hemoglobin is separated
from the red cell structure by ultraltration and purication
[3]. A number of processes exist to then stabilize the hemoglobin compound and prepare it for use. These include crosslinking, pyridoxylation, polymerization, or pegylation.
These processes prevent the dissociation of hemoglobin’s
four chain conguration into its basic alpha and beta dimers
[4]. Unfortunately, preparations have been limited by side
effects. Early formulations caused nephrotoxicity thought to
be secondary to red cell stromal fragments in the hemoglobin. Encapsulated HBOCs were attempted but ran into problems with the host-defense systems (reticuloendothelial
system) [5]. Most recently, hypoxic vasodilation that normally occurs in hypoxic states has been theorized to be limited by HBOCs due to the deactivation of this reex by the
scavenging of nitric oxide by the HBOC compounds causing
problematic vasoconstriction. Because of these drawbacks,
there is not currently a HBOC that can replace our current
standard of care using transfusion of red blood cells.
However, each trial has given us new information to use and
incorporate into the next possible product. There is still hope
and products in the pipeline (Table16.1).
Peruorocarbons, or PFCs, are chemically inert compounds where uorine replaces hydrogen atoms. They are
water insoluble which requires a lipid emulsication system
to be utilized. PFCs act as solvents for oxygen, and unlike
the coupling reaction and relationship of hemoglobin, the
amount of oxygen that can be dissolved follows a linear
© Springer Nature Switzerland AG 2021
C. S. Scher et al. (eds.), Essentials of Blood Product Management in Anesthesia Practice,
https://doi.org/10.1007/978-3-030-59295-0_16
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Table 16.1 Examples of HBOCs
Name Description
Diaspirin crosslinked Hb,
HemAssist
Hemopure (HBOC-201) Polymerized bovine Hb
PolyHeme Pyridoxylated polymerized Hb from
MP4OX PEG-conjugated human Hb
rHb1.1, rHb2.0 Recombinant human Hb (from E.coli)
Sanguinate PEG carboxylated bovine Hb
Chemically cross-linked Hb alpha
chains
outdated human blood
progression and obeys Henry’s law and is related directly
with PO2 [6]. However, PFCs have fairly short half-lives
(2–4h), and the necessary emulsion limits how quickly the
compound can be administered. A number of side effects
were seen in early clinical trials with PFCs, but the etiology
of the problems is unclear. A u-like illness was often seen
after administration as well as thrombocytopenia, which
likely occurred due to the emulsion’s effects on the platelets’
surface [6]. Initially, one PFC was approved for use in ischemic tissue situations (Fluosol); however, it was later pulled
due to lack of protability [7]. Currently, there does not
appear to be many trials in the pipeline for PFCs.
Most Benecial Uses forOxygen Carriers
Currently
There are currently no oxygen carriers approved by the FDA
for use in the USARight now, the only way to obtain one is
through the US Food and Drug Administration (FDA)
Expanded Access Protocol. Specically, the use of the unlicensed OC HBOC-201 (Hemopure) may be approved for
life-threatening anemia in patient populations where allogenic red blood cell transfusion is not an option [8]. Of note,
Hemopure is currently used in Russia and South Africa [9].
act with and inactivate endothelial nitric oxide, which is a
potent vasodilator [10].
Other effects on the cardiovascular system have also been
seen. One of these effects is an increase in myocardial infarctions in patients receiving HBOCs. Obviously, this is a worrisome complication, but the etiology is not fully known. It
does not appear that the scavenging of nitric oxide compounds is fully responsible for this phenomenon. In fact, in
studies where HBOCs were infused directly into coronary
arteries, no increase in vasoconstriction was seen [11].
Changes in coagulation and concern for coagulopathy
also have surrounded the use of HBOCs. Possible etiologies
for coagulopathy include dilutional coagulopathy and hypocalcemia, oxidation of the compound to methemoglobin and
subsequently inhibiting platelet aggregation, large molecular
weight molecules (HBOCs) complexing with von Willebrand
factor and speeding its elimination, and lastly nitric oxide
scavenging as mentioned previously [12].
One side effect that has been seen in early trials that may
be improved or eliminated in more recent trials is nephrotoxicity. Stroma-free hemoglobin caused excess glomerular ltration of hemoglobin dimers, resulting in acute tubular
necrosis and oliguria.
In addition to the above concerns, HBOCs and free hemoglobin have been implicated in a multitude of other possible complications: interference of macrophage function, GI distress, iron
deposition, neurotoxicity, antigenicity, and alterations on a number of clinical laboratory tests (bilirubin, creatinine kinase, magnesium, uric acid, and gamma- glutamyltransferase) [13].
The main side effects of PFCs were u-like reactions and
symptoms likely secondary to the cytokine-mediated effects
of the compounds and platelet sequestration in the spleen
and liver [3].
Outlook andFuture Development
Side Eects andChallenges ofOxygen
Carriers
The issues surrounding HBOCs have led to most trials
being discontinued and preventing further studies from
taking off. Some of the side effects were mentioned earlier,
but a number of different complications have been noted.
One of the main and most seen effects of HBOCs given at
therapeutic doses is systemic hypertension. Blood pressure
seems to increase without a corresponding increase in cardiac output. This hypertension also occurs in the pulmonary vasculature. So, in sum, increases are seen in SVR,
PVR, MAP, and pulmonary vasculature resistance index,
and a concomitant decrease is seen in cardiac output. The
most commonly accepted explanation is that HBOCs inter-
Unfortunately, no current oxygen carriers are FDA approved
for use in the United States. Although there are some companies pursuing this avenue for oxygen delivery, the side effects
and inability for previous products to be proven safe and
effective have limited further development. Further HBOC
compounds will have to address the nitric oxide scavenging
and molecular size and properties of the hemoglobin molecule. It is not currently known whether PFCs will have a role
in the future blood substitute world.
One exciting and new possibility is the culturing of red
blood cells invitro. Advances using hematopoietic progenitor cells from sources such as umbilical cord blood and stem
cells make this theoretically possible. As does the prospect of
creating immortalized adult erythroid progenitor cells.
However, many roadblocks exist from the science and regulatory aspects before this can become a real possibility [14].
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